ENDOCRINE DISRUPTORS

ENDOCRINE DISRUPTORS 1

ENDOCRINEDISRUPTORSSolutions to new challenges

2 ENDOCRINE DISRUPTORS

Introduction 1

1. Endocrine disruptors 31.1. The hormone or endocrine system 31.2. What are endocrine disruptors and how do they act? 61.3. Effects on human health and wildlife 151.4. Hazardous chemicals and activities 241.5. Exposure to endocrine disruptors in Spain 28

2. Case studies 372.1. Alkylphenols (APEs) 372.2. Biocides 302.3. EPOXY RESINS – Bisphenol A (BPA) and Epichlorohydrin 422.4. Mercury 442.5. Pesticides 47

3. Regulatory framework 493.1. EU regulations 493.2. National regulations 51

4. Proposals 53

October 2012

Published by: Instituto Sindical de Trabajo, Ambiente y Salud (ISTAS)ISTAS is a non-profit, technical foundation promoted by a major Spanish trade union confederation (CC.OO.) for the promotion of occupational health and environmental protection.

Author: Dolores Romano Mozo

Acknowledgements The author wishes to express her gratitude to Marieta Fernández, Nicolás Olea, Silvina Rabach, Jacinta Romano and Tatiana Santos for their useful comments and remarks.

Furthermore the author would like to thank Ninja Reinekey Genon Jensen for her support and trust.

This book has been published with the financial support of the EuropeanEnvironment and Health Initiative (EEHI).

Graphic Designer: teresacanal.com

Photography provided by: rakelfoto.com and istockphoto.com

English translation: Agustín González GarcíaTranslation reviewed by Susanna Sharpe

Printer: Gráficas SansueñaPrinted with vegetable inks on 100% recycled, chlorine-free paper

Legal deposit for this edition in Spain: V-1100-2013


PREfaCE

The prevention of occupational and environmen-tal risks associated with the exposure to endo-crine disruptors (EDC) represents a true challenge for experts worldwide.

Traditional risk assessment methods included in current legislation prove inadequate to protect human health and the environment from EDCs, given the specific characteristics of these com-pounds:

• EDC may have effect at very low doses• Certain developmental periods are particularly

vulnerable to endocrine disruption and expo-sure in such periods may have lifelong health effects

• EDCs do not have a linear dose-effect relation• EDCs may have a combined effect• Health effects may affect future generations• Harmful effects of EDC may have long latency

periods • Ubiquity of exposure• Impossibility to establish a safe threshold of

exposure for EDCs

Protection from the effects of EDCs represents a new challenge that calls for a new paradigm based on the application of the precautionary principle* and the adoption of urgent measures.

Such measures include:

• Avoiding exposure to EDCs of children, preg-nant women, breastfeeding mothers and women in reproductive age

• Eliminating or reducing exposure to EDCs as much as possible

• Implementing new methods of identification and statistical sampling that include all chem-icals with potential to interfere with hormone systems

* The Wingspread Statement on the Precautionary Principle summarizes the principle as follows: “When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically.” The Wingspread Conference on the Precautionary Principle was convened by the Science and Environmental Health Network. (Science and Environmental Health Network. The Precautionary Principle: A Common Sense Way to Protect Public Health and the Environment: http://www.mindfully.org/Pre-caution/Precautionary-Principle-Common-Sense.htm)


Endocrine disruptors are chemicals that interfere with human and animal hormone systems, and are capable of altering hormone balance and em-bryo development, with the risk of adverse effects on the health of organisms and their offspring. This section considers the following aspects of endocrine disruption:

1.1 The hormone or endocrine system.1.2 What are endocrine disruptors and how do

they act?1.3 Effects on human health and wildlife.1.4 Hazardous chemicals and activities.1.5 Exposure to endocrine disruptors in Spain.

1. ENDOCRINE DISRUPTORS

1.1. The hormoneor endocrine systemIn order to understand EDCs and how they affect us, we turn to a summary of the characteristics and functions of hormones and the endocrine system.

The hormone or endocrine system functions as a communication system. In many-celled organ-isms, communication between cells is essential for their coordinated function. Such communica-tion is based on chemical signals.

Neighboring cells communicate via surface mole-cules and special junctions, whereas communica-tion between distant cells is carried out through the release of chemical signals, hormones that activate target cells and interact with specific receptors.1 Chemical signals travel through the bloodstream (circulatory system) to reach target cells.

anatomical structure of the endocrine system

Cells responsible for signal (hormone)2 releases are called ENDOCRINE CELLS and are basically found in three locations:

• Endocrine cells that make up a specific organ, or ENDOCRINE GLAND (see Figure 1).

1 There are four types or categories of hormone secretion: • autocrine signaling: a cell secretes a hormone that binds to autocrine receptors on the same cell (e.g.: epidermal

growth factor) • Paracrine signaling: the target cell is near the signal releasing cell (e.g.: prostaglandins in the diffuse neuro-endocrine system). • Endocrine signaling: target cells are located away from the signal releasing cells (hormones are secreted directly into

the bloodstream). • Synapse: direct communication between two nerve cells. The signal releasing cell, in this case a neuron, is in direct

contact with the target cell (e.g.: another neuron, a myocyte, etc.) and passes an electrical or chemical signal to it (neuro-transmitter) that might be shared with the endocrine system. Neurotransmission is a nearly instantaneous process.

2 Hormones are classified into four main type of cells: - Hormones derived from amino acids (e.g.: adrenaline, noradrenaline, thyroxine) - Peptides (enkephalin, vasopressin) - Proteins (insulin, growth hormones) - Steroids (cortisol, progesterone, estradiol, testosterone) Most chemicals signals are hydrosoluble, they also diffuse easily and interact with surface molecules. However, steroids

and thyroxine are hydrophobic and react with intracellular receptors through cell membranes.


figure 1. Endocrine glands

• Endocrine cells that form small groups in oth-er specialized organs (ovary, testes, pancreas).

• Endocrine cells individually dispersed among epithelial tissue cells, especially in the diges-tive and respiratory systems, part of the DIF-FUSE NEUROENDOCRINE SYSTEM.

Hormone action mechanisms

Hormones may act as enzymes through direct ac-tion on specific chemical reactions. They can also act on a target cell joining a specific receptor. Ac-tion mechanisms depend on the type of receptor:

• Membrane receptors: located in cell mem-branes, these are specialized integral mem-brane proteins that take part in communica-tion between the cell and the outside world. The binding of the receptor with the mem-brane may alter the membrane’s permeability (the basis of nervous impulse transmission in neurons; insulin and glucocorticoids act in the same way). It can also modify a second intra-cellular transmitter (AMPc or GMPc).3

• Intracellular receptors: located inside the cell, they are activated by hormones and are trans-ported to the nucleus, where they stimulate synthesis of a new effector protein.

All vertebrates possess the same endocrine glands that control development, growth, and re-production, among other functions.

Each endocrine gland secrets a specific amount of a hormone at a given time. That hormone cir-culates through the bloodstream in very small amounts.

Hormones are extremely effective chemicals. The amount of a given hormone needed to regulate a metabolic function is incredibly small. For exam-ple, estradiol, the most potent of the estrogens, acts in concentrations of parts per billion (pg/g, pg/ml).

Hormone concentrations in the blood vary from person to person, depending on age, sex, and reproductive cycle or health conditions. Each person has a specific hormonal balance. Table 1

3 Cyclic Adenosine Monophosphate (cAMP (cAMP) and Cyclic Guanosine Monophosphate (cGMP)

PINEAL GLANDHYPOTHALAMUS

HYPOPHYSIS

THYROID GLANDPARATHYROID

THYMUS

PANCREAS

TESTIS

OVARY

ADRENAL(SUPRARENAL)


4 Laura N. Vandenberg, Theo Colborn, Tyrone B. Hayes, Jerrold J. Heindel, David R. Jacobs, Jr., Duk-Hee Lee, Toshi Shioda, Ana M. Soto, Frederick S. vom Saal, Wade V. Welshons, R. Thomas Zoeller, and John Peterson Myers. Hormones and Endocrine-Dis-rupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses. Endocrine Reviews, March 14, 2012 er.2011-1050.

shows the range of endogenous concentrations of some hormones.4

Hormones regulate different functions with various degrees of complexity. Their functions include:

• Acting as simple information transmitters.• Controlling maximum and minimum levels of

metabolic function.• Carrying out control functions by feedback.• Controlling complex processes such as the

menstrual cycle.• Regulating the development of the mammary

glands.• Regulating metabolic levels.• Regulating embryogenesis (embryo formation

and development).

The hypothalamic-pituitary-gonadal axis (HHG) controls ovarian hormone synthesis via releas-ing factors (GnRH) and gonadotropic hormones (LH, FSH); ovarian steroids have a negative feed-back effect on the hypothalamus and the hypo-phisis (pituitary gland), both located in the brain. The hypothalamic-pituitary-adrenal axis (HPA or HTPA axis) is an essential part of the neuroendo-crine system that controls stress and regulates body processes such as digestion, the immune system, sexuality, and energy metabolism.

Hormones control the growth of the nervous and immune systems in the embryo and program the functions of tissues and organs such as the liver, blood, kidneys, and muscles, which work differ-ently in men and women. In order that these sys-tems develop normally, the embryo must receive correct and precisely timed hormonal signals. The disruption of signals during a critical devel-opmental period can have serious consequences for the organism during the rest of its life.

The endocrine and nervous systems interact through the hypothalamus, the pituitary, and the network of neurotransmitters that connects them. Both systems interact with the immune system through cytokines, a category of signaling molecules (hormones). Given the close interac-tion between the three systems, some scientists refer to them as the neuro-immune-endocrine system.

Table 1. Concentration of some endogenous hormone in humans

Hormone Free concentrations(women)

Total concentration(women)

Free concentrations(men)

Total concentration(men)

CortisolEstradiol

Progesteron

InsulinGHProlactinTestosteronThyroid TSH

20-300 ng/ml0,5-9 pg/ml (adult female)

9-150 pg/ml (adult)8-30 pg/ml (10-35 pM)

0,5-5 µU/ml

<20 pg/ml (prepuberal)20-800 pg/ml (premenopausal)<30 pg/ml (postmenopausal)0,2-0,55 ng/ml (prepuberal)0,02-0,80 ng/ml (follicular phase)0,90-4 ng/ml (luteal phase)<0,5 ng/ml (postmenopausal)0-250 pmol/liter2-6 ng/ml0-15 ng/ml

20-300 ng/ml

0,3-250 ng/ml8-30 pg/ml (10-35 pM)

0,5-5 µU/ml

10-60 pg/ml (adult)

0,1-0,4 ng/ml (prepu-beral)0,2-2 ng/ml (adult)

0-250 pmol/liter2-6 ng/ml0-10 ng/ml

Source: Laura N. Vandenberg, Theo Colborn, Tyrone B. Hayes, Jerrold J. Heindel, David R. Jacobs, Jr., Duk-Hee Lee, Toshi Shioda, Ana M. Soto, Frederick S. vom Saal, Wade V. Welshons, R. Thomas Zoeller, and John Peterson Myers. Hormones and Endocrine-Disrupting Che- micals: Low-Dose Effects and Nonmonotonic Dose Responses. Endocrine Reviews, March 14, 2012 er.2011-1050.


References

Center for Bioenvironmental Research. (2002) Environmental Estrogens and Other Hormones. Louisiana: Tulane and Xavier Universities. http://www.som.tulane.edu/cbr/ecme/eehome/default.html

Colburn, T., J.P. Myers, and D. Dumanoski. (2001) (Our Stolen Future). Nuestro futuro robado ¿Ame-nazan las sustancias químicas sintéticas nuestra fertilidad, inteligencia y supervivencia? Madrid: Ecoespaña Editorial.

Kortenkamp, Andreas, Olwenn Martin, Michael Faust, Richard Evans, Rebecca McKinlay, Frances Orton, and Erika Rosivatz. (2011) State of the Art Assessment of Endocrine Disrupters. Final Report. Project Contract Number 070307/2009/550687/SER/D3. 23.12.2011.

SUMMaRYTHE HORMONE OR ENDOCRINE SYSTEM

• Is a complex signaling system that regulates vital bodily functions, including embryonic development.

• Is closely related to the nervous and immune systems.• Is made up of glands, hormones, and hormonal receptors.• Hormones are chemical substances that act as messengers.• One hormone can regulate vastly different functions in different body organs.• Hormones are highly effective and act at very low concentrations.• Each human being has a different hormonal balance.• The hormone system coordinates with the nervous and immune systems.

1.2. What are endocrine disruptors and how do they act?

Endocrine disruptors, environmental estrogens, xenoestrogens, endocrine modulators, envi-ronmental hormones, hormonally active com-pounds, philoestrogens

The terms listed above all refer to endocrine dis-ruptors, that is, chemicals capable of altering hor-monal balance and the development of embryos, and hence capable of causing adverse effects in living organisms and their offspring.

The ability of certain chemicals to interfere with the human hormone system was discovered 40 years ago when the pharmaceutical drug di-ethylstilbestrol (DES) was used to prevent mis-carriage in pregnant women. However, the term endocrine disruptor chemical (EDC) was coined some 50 years later, in 1991, during the Wing-spread Conference,5 when a group of endocri-nologists, toxicologists, epidemiologists, and other health experts met to assess harmful ef-fects on humans and wildlife observed in epide-miological studies in the Northern Hemisphere. These included damage to the reproductive and immune systems and certain types of cancer in hormone-dependent organs, among other health problems. Participants hypothesized that the ad-verse effects were due to changes in embryonic and fetal development brought on by exposure

5 Bern, H et al. Statement from the work session on chemically-induced alterations in sexual development: the wildlife/hu-man connection in Eds. T Colborn and C Clement. Chemically-Induced Alterations in Sexual and Functional Development: The Wildlife/Human Connection. NJ, U.S: Princeton Scientific Publishing Co., 1992.


to chemical pollutants. Those pollutants were de-fined as endocrine disruptors. Experts expressed their concern about the public health and envi-ronmental implications of such findings.

The term endocrine disruptor is broadly defined as “an exogenous agent that interferes with the production, release, transport, metabolism, bind-ing, action or elimination of natural hormones in

the body responsible for the maintenance of ho-meostasis and the regulation of developmental processes.”6

The catalogue of endocrine disruptors is exten-sive and continues to grow. It includes synthe-sized chemical products, as well as substances found in the natural environment (see section 1.5).

6 Kavlock, R. J. et al. Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U. S. EPA-sponsored workshop. Environ. Health Perspect.1996; 104 (Suppl. 4), 715–740.

ER, estrogen receptor; mER, membrane-associated ER;AR, Androgen receptor; ERR, estrogen related receptor; PPAR, peroxisome proliferator-activated receptor; PRGR, progesterone receptor; RXR, retinoid X recep-tor; TH, thyroid hormone; TRE, thyroid response element.

Source: Adapted from Laura N. Vandenberg, Theo Colborn, Tyrone B. Hayes, Jerrold J. Heindel, David R. Jacobs, Jr., Duk- Hee Lee, Toshi Shioda, Ana M. Soto, Frederick S. vom Saal, Wade V. Welshons, R. Thomas Zoeller, and John Peterson Myers. Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses. Endocrine Reviews, March 14, 2012 er.2011-1050.

Chemical Use EDC action Affected endpoint

Atrazine Herbicide Increase of aromatase expression

Male sex differenciation /develop-ment

Bisphenol A (BPA) Plastics, thermal papers, epoxy resins Binds ER, mER, ERRy, PPARy, may weakly bind TH recep-tor and AR

Prostate, mammary gland, braindevelopment and behavior,reproduction, immunesystem, metabolism

Chlorpyrifos Insecticide Antiandrogenic Acetylcholine receptor binding (brain)

Dioxin (TCDD) Industrial byproduct Binds AhR Spermatogenesis, immune function and oxidative stress, tooth and bone development, female reproduction, mammary gland, behavior

Hexachlorobenzene Fungicide Modulates binding of ligand to TRE, weakly binds AhR

Anxiety and aggressivebehaviors

Methoxychlor Insecticide Binds ER Immune system

4-Methylbenzylidinecamphor

UV screen Weakly estrogenic Sexual behavior

Methyl paraben Preservative Estrogenic Uterine tissue organization

Nonylphenol Detergents Weakly estrogenic Testosterone metabolism

PCB180 Industrial lubricant,coolant

Impairs glutamate path-ways, mimics estrogen

Diabetes (humans)

Perchlorate Fuel, fireworks Blocks iodide uptake, alters TH

TSH levels (humans)

Tributyltin oxide Pesticide, wood preservation Binds PPARy Obesity

Triclosan Antibacterial agent Antithyroid effects, an-drogenic and estrogenic activity

Altered uterine responses toethinyl estradiol

Table 2. action principles of some EDCs and examples of affected endpoints


Mechanisms and action principles

It is a priority for researchers in this field to un-derstand the action principles and mechanisms of endocrine disruptors. Recent years have seen great advances in which researchers have man-aged to describe different ways in which en-docrine disruptors can alter hormonal balance. Those processes include:

• Mimicry of hormones: for example, EDCs that act like estrogen are known as environmental estrogens; examples are DDT, some PCBs, and many philoestrogens, nonsteroidal chemical compounds found in vegetables that are simi-lar to human estrogens.

• antagonizing hormone effects: for example, the anti-estrogenic action of some PCBs or PCBS, such as vinclozolin (dicarboximide fun-gicide).

• altering hormonal binding and metabolism patterns: for example, the effects of the flame retardant PBDE-99, which alters the synthesis of thyroid hormone (TH).

• Modulating the levels of hormone receptors: for example, bisphenol A (BPA), found in some plastics and epoxy resin, which interacts with estrogen receptors.

The most researched action mechanisms in-clude:7, 8

• Estrogenicity/ anti-estrogenicity• Androgenicity/ anti-androgenicity• Thyroid alteration• Alteration of hormone receptors: estrogenic

receptor (ER), membrane-associated estro-gen receptor (mER), androgenic receptor (AR), estrogen-related receptor (ERR), peroxisome proliferator-activated receptor (PPAR), proges-terone receptor (PR), retinoid X receptor (RXRs); aryl hydrocarbon receptor (AHR)

• Alteration of retinoic acid, PPAR, and vitamin D routes

• Alteration of target tissues in the brain and in the reproductive and cardiovascular systems

• Pancreatic ß-cell (beta-cell) dysfunction• Endogenous inhibition of hormone metabo-

lism• Multiple hormone-modifying effects

EDCs are considered “chemical chameleons,” that is, a single EDC has different action mechanisms depending on its concentration (see Table 2).

Therefore, high doses of dioxins can be fatal, but very low concentrations (such as the ones to which the population is exposed through contaminated food products) may significant-ly increase the risk of reproductive anomalies in women.9

High levels (100–1,000,000 nanomolar) of hexachlorobenzene (HCB) suppress the an-drogenic activity of prostate cells, whereas low doses (1 nanomolar) increase this activity.10

For instance, in utero exposure of female mice to low doses (1ppb) of DES can cause obesity in adult offspring, while mice exposed in utero to higher doses exhibit weight loss at the same age.11

The same EDCs may also have different action mechanisms depending on the specific develop-mental stage of the affected tissue:

In order to obtain a uterotrophic response (affecting the uterus) in adult mice, it is nec-essary to administer 100 mg/kg/day of BPA. However, only 25 ng/kg/day of BPA (4,000,000 times less) during pregnancy may cause a re-sponse in mammary ductal tissue.

adverse effects may vary depending on the time of exposure and the hormonal balance of the exposed individual, which is determined by age and sex, among other factors.12

7 Andreas Kortenkamp, Olwenn Martin, Michael Faust, Richard Evans, Rebecca McKinlay, Frances Orton and Erika Rosivatz. State of the Art Assessment of Endocrine Disrupters. Final Report. Project Contract Number 070307/2009/550687/SER/ D3. 23.12.2011.8 Miquel Porta and Duk-Hee Lee. Review of the science linking chemical exposures to the human risk of obesity and diabe-

tes. CHEM Trust, 2012.9 Laura Vandenberg. Opinion: ‘There are no safe doses for endocrine disruptors’. Environmental Health News. March 15, 2012.10 Myers P. & Hesler W. Does ‘the dose make the poison? Extensive results challenge a core assumption in toxicology. Envi-

ronmental Health News. April 30, 2007.11 Miquel Porta and Duk-Hee Lee, Op. Cit.12 Colborn T. Commentary: setting aside tradition when dealing with endocrine disruptors. ILAR J. 2004; 45(4): 394-400.


Periods of particular vulnerability/Time of exposure

Knowing the specific time of exposure in devel-oping organisms is essential in assessing the nature, gravity, and subsequent evolution of EDC effects, as they are different in embryos, fetuses, newborns, and adults. If EDC exposure takes place during critical periods (like early developmental stages characterized by rapid cellular differentia-tion and organogenesis) damage is irreversible.13

There is substantial evidence about the particu-lar sensitivity of developing organisms to chemi-cals that interfere with hormone activity during critical (in utero) phases of organogenesis. Effects are often irreversible and remain in affected or-ganisms for the rest of their lives. Furthermore, the latency period (the time between exposure and manifestation of the first symptoms) can be lengthy.14

Exposure to biologically active chemicals in con-centrations that affect hormones can lead to a series of effects that vary progressively through different developmental stages of the organism. Similarly, these effects might differ from the re-sponse observed during exposure to high doses of the same chemical, or from responses in fully developed individuals.15

While hormonal effects are mostly associated with signal activation and are reversible in adults, untimely exposure to hormones during fetal or-gan development primarily affects the structure and function of organs, causing irreversible dam-age.16

The effects of in utero exposure to EDCs are not necessarily evident at birth; they may remain latent for years or become apparent in the off-spring of exposed individuals, so that the conse-quences of exposure occur more frequently in the offspring than in the exposed parents. The genetic mechanisms by which the effects of exposure pass to future generations are known as epigenetic changes. Some examples are listed below:17

• Androgen antagonists such as pesticides and phthalates can interfere with androgenic ac-tion during the first stage of male fetal male development. The decrease of androgenic ac-tion, when seen in laboratory animals, only becomes evident in adulthood and its effects include malformation of reproductive organs. Most of these effects are irreversible.

• Epidemiological studies show that exposure to dioxins (TCDD) during the perinatal period has a negative impact on the quality of sperm, while exposure in adult life has no effect on sperm quality.

• Estradiol and estrogenic chemicals may inter-fere with the KiSS-1 peptide system in rodents during the neonatal period and affect the age of onset of puberty.

• The development of the female reproductive system is programmed during fetal develop-ment; this framework can be disrupted by chemicals such as DES, with multiple irrevers-ible consequences.

• Some hormone-related cancers (breast, pros-tate, testicular, ovarian, and endometrial) may originate during either fetal development or puberty. During these periods, there is a high level of sensitivity to chemical exposure in-volving known carcinogens in these types of cancers.

• The action of thyroid hormones during in ute-ro development is essential in multiple organs. Those include the brain and the neuroendo-crine system. The interruption of thyroid ac-tion caused by chemical exposure during this period can have irreversible adverse effects.

• Many species have multiple of periods of vul-nerability, among them, grasshoppers, certain amphibians, and reptiles, which are extremely sensitive to EDCs.

13 Marieta Fernández. FUNDAMENTOS DE TOXICOLOGIA. Seminario de actualización en Toxicología Laboral. ISTAS, Madrid, 21 de septiembre de 2011.

14 Bern, H et al. Op. Cit.15 Laura Vandenberg. Op. Cit.16 Ana M. Soto and Carlos Sonnenschein. Environmental causes of cancer: endocrine disruptors as carcinogens. Nature Re-

views Endocrinology 6, 363-370 (July 2010) | doi:10.1038/nrendo.2010.87.17 Bern, H et al. Op. Cit.


Low-dose effects

Many EDCs cause adverse effects at very low levels of exposure, equivalent to the amounts to which the population is generally exposed. As described previously, these low-dose effects may differ from effects associated with the same chemical at higher doses.

Table 3 shows the concentrations at which an estrogenic effect is observed in a selection of industrial chemicals, according to the E-SCREEN assay. Concentrations are expressed in the nano-micromolar range (pg/g to ng/g).18

A study on human exposure to persistent organic pollutants with estrogenic capability (PCBs, DDT, HCB) in Catalonia (Spain) detected concentra-tions of such chemicals in an average range of 20–300 ng/g in 90 percent of the population (Figure 2),19 implying that the exposed population presented organic levels of EDC that might cause negative health effects.

Dose-response curve

Another significant characteristic of EDCs is that they do not have a linear dose-response pattern.

“Dose makes the poison” is the principle behind conventional chemical-risk assessment, which proves valid for most chemicals (see Figure 3). Safe exposure levels are calculated according to that principle. Toxicity testing for specific ef-fects, for example, estrogenicity, is carried out by decreasing doses of a given chemical until the No Observable Adverse Effect Level (NOAEL) is reached.

NOAEL denotes the level of exposure at which there is no biologically or statistically significant increase in the frequency or severity of any ad-verse effects in the exposed population when compared to its appropriate control. Safe levels of exposure are determined by adding a safety fac-tor to the NOAEL.

Source: Ana M. Soto, Carlos Sonnenschein, Kerrie L. Chung, Mariana F. Fernández, Nicolás Olea, and Fátima Olea Serrano. The E-SCREEN Assay as a Tool to Identify Estrogens: An Update on Estrogenic Environmental Pollutants. Environ Health Perspect 1 03 (Suppl 7):113-122 (1995).

Table 3. Estrogenic effects of industrial chemicals measured by the E-Screen assay

18 Ana M. Soto, Carlos Sonnenschein, Kerrie L. Chung, Mariana F. Fernández, Nicolás Olea, and Fátima Olea Serrano. The ES-CREEN Assay as a Tool to Identify Estrogens: An Update on Estrogenic Environmental Pollutants. Environ Health Perspect

1 03(Suppl 7):113-122 (1995).19 Miquel Porta, Elisa Puigdomènech, Magda Gasull y Magda Bosch de Basea. Distribución de las concentraciones séricas de compuestos orgánicos persistentes (COPs) en una muestra representativa de la población general de Cataluña. Barce-

lona: Departamento de Salud de la Generalitat de Cataluña, IMIM y Universidad Autónoma de Barcelona, 2009.

Chemical Concentrationa APE, %c APP, %

EstradiolPhenol4-Ethylphenol4-Propylphenol4-sec-Butylphenol4-tert-Butylphenol4-tert-Pentylphenol4-Isopentylphenol4-Butoxiphenol4-Hexyloxyphenol4-Hydroxibiphenyl4,4-Dihydroxybiphenyl1-Naphtol2-Naphtol5,6,7,8, -Tetrahydronaphtol-26-Bromonaphtol-25-Octylphenol4-NonylphenolNonylphenol, technical grade t- Butylated hydroxyanisole Benzylbutylphthalate

30 pM10 µMb

10 µMb

10 µM10 µM10 µM10 µM10 µM10 µMb

10 µMb

10 µM10 µM10 µMb

10 µMb

10 µMb

10 µM100 nM1 µM10 µM50 µM10 µM

1000517767110593008784000381001001023090

100------0,00030,00030,00030,0003----0,00030,0003--------0,030,0030,00030,000060,0003


figure 2: Concentrations of 7 Persistent organic Pollutants (POP) in more than 90% of monitored indi-viduals in Catalonia

Source: Miquel Porta, Elisa Puigdomènech, Magda Gasull y Magda Bosch de Basea. Distribución de las concentraciones séricas de compuestos orgánicos persistentes (COPs) en una muestra representativa de la población general de Cataluña. Barcelona: Departa-mento de Salud de la Generalitat de Cataluña, IMIM y Universidad Autónoma de Barcelona, 2009.

figure 3. Dose -response curve of barbiturates and benzodiazepines

20 Myers P. & Hesler W. Op. Cit.10.

p.p’-DDT

ng’g

p.p’-DDE PCBs 138 PCBs 153 PCBs 180 HCB ß-HCH0

250

750

1.250

500

1.000

1.500

1.750

2.000

Fuente: Marieta Fernández. FUNDAMENTOS DE TOXICOLOGIA. Seminario de actualización en Toxicología Laboral. ISTAS, Ma-drid, 21 de septiembre de 2011.

However, many EDCs do not follow the dose-response pattern, and have a nonlinear (U or in-verted U-shaped curves) pattern, which indicates that they may cause toxic effects at high doses, no effects at medium doses, and adverse effects at low doses (see Figures, 4, 5, and 6).20

Coma

Death

Barbiturates

Benzodiazepines

Anestesia

Hypnosis

Sedation


figures 4, 5 and 6. Examples of non-monotonic dose-response curves

Source: Myers P. & Hesler W. Does ‘the dose make the poison? Extensive results challenge a core assumption in toxicology. En-vironmental Health News. April 30, 2007.

Standard toxicity tests included in current EDC regulations do not detect adverse effects caused by exposure to low doses because no adverse ef-fects are observed at higher doses and therefore no further testing is carried out at low doses (see Figure 7).

figure 7. Calculation of exposure levels in stand-ard toxicity tests

100

125

50

75

25

0

DEHP (mg/kg/day)

0

0.01

5

1.215

0.13

5 15 135

0.04

5 5

0.40

5 45 405

arom

atas

e ac

tivity

(fmol

/mg

prot

ein/

15 m

in)

30

10

Control 0.1 nMBPA

1 nMBPA

10 nMBPA

100 nMBPA

20

0

Adapted from Wetherill et al.

Pros

tatic

ade

noca

rcin

oma

Cell

Prol

ifera

tiona

Inde

x

150

200

50

1 100 10,000 1,000,000

100

0

nanoMolar HCB

% a

ctiv

ity co

mpa

red

to co

ntro

l (no

HCB

)

Adapted from Ralph et al. 2003

increase

decrease

Source: Laura N. Vandenberg, Theo Colborn, Tyrone B. Hayes, Jerrold J. Heindel, David R. Jacobs, Jr., Duk-Hee Lee, Toshi Shioda, Ana M. Soto, Frederick S. vom Saal, Wade V. Welshons, R. Thomas Zoeller, and John Peterson Myers. Hormones and Endocrine-Dis-rupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses. Endocrine Reviews, March 14, 2012 er.2011-1050.

Therefore, it is impossible to establish a safe level of exposure to EDCs that have nonlinear dose-response curves. In addition, safe exposure levels to these chemicals that have been established for other toxic effects do not guarantee protection from endocrine disruption.

Mixes / combined effects

Another distinctive characteristic of EDCs that raises concern among researchers is that adverse effects might be the result of combined action by several chemicals that do not cause negative health effects separately, yet when mixed may cause a paradoxical reaction in the form of syner-gistic, antagonistic, or additive effects. This is par-ticularly significant since in real life, the popula-tion is exposed to a low-concentration “cocktail” of multiple chemicals, yet risk-assessment pro-cedures that are part of the existing regulatory framework only consider exposure to individual chemicals.

100

DOSE

00

RESP

ON

SE

NOAEL

LOAEL“safe” dose

Safety factors

MTD


21 Andreas Kortenkamp, Thomas Backhaus and Michael. Faust State of the Art Report on Mixture Toxicity. Final Report. Ex-ecutive Summary. 22 December 2009. Study Contract Number 070307/2007/485103/ETU/D.1.

22 Rajapakse N, Silva E, Kortenkamp A 2002. Combining Xenoestrogens at Levels below Individual No-Observed-Effect Concentrations Dramatically Enhances Steroid Hormone Action. Environ Health Perspect. 110:917-921. http://dx.doi.org/10.1289/ehp.02110917.

23 Jesus M. Ibarluzea, Mariana F. Fernandez, Loreto Santa-Marina, Maria F. Olea-Serrano, Ana M. Rivas, Juan J. Aurrekoetxea, Jose Exposito, Miguel Lorenzo, Pablo Torne, Mercedes Villalobos, Vicente Pedraza, Annie J. Sasco & Nicolas Olea. Breast cancer risk and the combined effect of environmental estrogens. Cancer Causes and Control. 15: 591-600, 2004.

Figure 8 shows the potential of different pesti-cide combinations to inhibit the activity of ace-tylcholinesterase (an enzyme involved in neuro-transmission).21

figure 8. Combined effects of pesticides on on the inhibition of acetylcholinesterase (aChE) activity

Source: Andreas Kortenkamp, Thomas Backhaus and Michael. Faust State of the Art Report on Mixture Toxicity. Final Report. Executive Summary. 22 December 2009. Study Contract Num-ber 070307/2007/485103/ETU/D.1.

Figure 9 shows that substances which might have a low estrogenic effect separately increase their estrogenic effect in combined exposures (MIX).22

figure 9. Combined estrogenic effects

50

40

30

20

10

0

60

AChE

act

ivity

(% co

ntro

l) (50% inhibition predicted)

CB+OPCB+CB OP+OP

antagonismadditionsynergism

crl+

cbn

crl+

cfs

cbn+

cfs

crl+

dzn

cbn+

mln

cbn+

dzn

dzn+

cfs

mln

+cfs

dzn+

mln

crl+

mln

Source: Rajapakse N, Silva E, Kortenkamp A 2002. Combining Xenoestrogens at Levels below Individual No-Observed-Effect Concentrations Dramatically Enhances Steroid Hormone Action. Environ Health Perspect. 110:917-921. http://dx.doi.org/10.1289/ehp.02110917

Several studies conducted by the University of Granada (Spain) on women in the Andalusia re-gion showed an increased risk of breast cancer caused by combined exposure to estrogenic pol-lutants, measured as a total load of xenoestro-gens (TEXB) in serum and fat tissue (Table 4).23

Table 4. Total xenoestrogens load (TEXTB) in se-rum and fat tissue of women with breast cancer and cases control

a GM, Geometric Mean; GSD, Geometric Standard Deviation b Assay Student’s t.c ng/g fat.d Estradiol equivalent picomolar (Eeq)/gr. of fat.

1 2 3 4 5 6 7 8 9 10 11 12 ES CA MIX0.0

0.2

0.4

0.6

0.8

1.0

Compound

Corr

ecte

d ab

sorb

ance

(aU

)

Cases (n = 198) Controls (n = 260)

GM GSDa GM GSD Pb

DDEc 326,86 2,78 307,34 3,62 0,57

Aldrinc 2,84 4,12 2,37 4,21 0,33

Endosulfan-etherc 0,79 1,95 0,75 1,81 0,66

Lindanc 6,12 2,84 5,82 3,02 0,67

TEXB-alphad 44,60 14,73 31,79 14,30 0,20

TEXB-betad 76,48 13,74 72,70 14,44 0,86

Source: Jesus M. Ibarluzea, Mariana F. Fernandez, Loreto Santa-Marina, Maria F. Olea-Serrano, Ana M. Rivas, Juan J. Aurrekoetxea, Jose Exposito, Miguel Lorenzo, Pablo Torne, Mercedes Villalobos, Vicente Pedraza, Annie J. Sasco & Nicolas Olea. Breast cancer risk and the combined effect of environmental estrogens. Cancer Causes and Control. 15: 591-600, 2004.

Safe exposure limits

As previously described, either there is no exact threshold of concentration for the development of endocrine disruption, or that level is different from the known safety limit for other toxicologi-cal effects.

Although a theoretical safety threshold could be established for a substance in specific individu-als, it is not possible to establish safety limits for a whole population given the different effects of EDCs on individuals, and the role in disease pro-cesses played by differences in exposure, whether endogenous or environmental.24


24 Bern, H et al. Op. Cit.

SUMMaRY

• Endocrine disruptors (EDCs) are chemicals capable of interfering with hormone balance.• They act at very low doses, have multiple action mechanisms, and comprise an extensive

group of substances with different chemical structures.• A single EDC may have different action mechanisms depending on its concentration and

on the specific developmental stage of the affected tissue. Adverse effects vary depend-ing on the time of exposure and the hormonal balance of exposed individuals, deter-mined by factors like sex and age.

• There are periods of particular vulnerability to EDC exposure. The most critical periods observed by researchers so far include the prenatal and perinatal. Effects of prenatal ex-posure might not develop until later in life. Adverse effects may also pass from one gen-eration to another through genetic programming, e.g., epigenetic changes.

• Many EDCs cause adverse effects at very low doses, equivalent to current exposure levels in the population. Low-dose effects might differ from adverse effects caused by high-dose exposures.

• The general population is exposed to EDC levels that may have serious effects on health.• The dose-poison rule does not apply to EDCs because many of these substances do not

have a linear dose-response pattern, but have curve patterns (U or inverted U), which im-plies they may have toxic effects at high doses, no effect at medium doses, and adverse effects at low doses. Therefore, standard toxicity tests mandated by existing regulations do not detect the effects caused by EDCs at low concentrations.

• No safe exposure limit can be established for EDCs with nonlinear dose-response curves. Safe exposure levels established for other effects do not guarantee protection from en-docrine disrupting effects.

• Adverse effects may be the result of combined action by different compounds that sepa-rately have no negative health impact, but when combined can cause a synergistic, an-tagonistic, or additive response.

• It is impossible to establish safe exposure thresholds for EDCs.

for all of the above reasons, EDCs must be considered chemicals without safe levels of exposure.


1.3. Effects on human health and wildlifeA significant body of scientific evidence shows that many EDCs studied to date have a wide range of effects on human health as well as on wildlife. This evidence is based on:

• Effects observed in wildlife species• In vivo (animal) and in vitro (cell culture) tests • Effects observed in humans• Epidemiological studies

A report issued by the European Commission in February 201225 summarizes the following effects of EDCs on human health and wildlife.

1.3.1. Effects on human health

1.3.1.1. Damage to reproductive health

Damage to the male reproductive system

Exposure to EDCs is associated with three ef-fects that are usually considered as a whole: (1) reduction of reproductive capability manifested by infertility and decrease of sperm quality; (2) changes in fetal development resulting in con-genital deformity of the male genital tract such as chryptorchidism (failure of testicular descent) and hypospadias (abnormal placement of the male external urethral orifice); (3) the presence of testicular germ-cell tumors.

Reduced sperm quality

Joint studies carried out in several European countries show a continuous reduction of sperm quality by year of birth, with younger men show-ing the worst indicators. Approximately 20 per-cent of young men in Denmark and Germany show sperm concentrations below the 20 million per mililiter limit established by the WHO.

Chryptorchidism

Chryptorchidism (failure of testicular descent) is a male congenital deformity that is most com-mon in newborn babies. The condition generally affects between 2 and 4 percent of children, but recent estimates show an increase of up to 9 percent in some countries. Researchers have ob-served an increased risk of chryptorchidism with prenatal exposure to DES, PCBs, polybrominated diphenyl ethers (PBDEs), heptachlor epoxide, hexachlorobenzene (HCB), and some pesticides, including DDT/DDE.

Hypospadias

Hypospadias affects between 0.2 and 4 percent of newborns. The action of androgenic hormones is essential to the proper development of the male external urethral orifice. A reduction of an-drogens causes the male urinary meatus to open anywhere along the urethral groove or even near scrotum.

Alterations in the female repro-ductive system

Exposure to EDCs, particularly during in utero de-velopmental stages, is associated with precocious puberty, reduced fecundity, pregnancy complica-tions, endometriosis, uterine fibroids (noncancer-ous tumors), as well as breast and ovarian cancer.

Precocious puberty

There is significant scientific evidence of the abil-ity of certain synthetic chemicals to alter the pro-gramming of puberty during vulnerable develop-mental periods.

25 Andreas Kortenkamp et al. Op. Cit.


Precocious female puberty has increased over the last decades. The average age at menarche in Western Europe and in the United States in the 1990s was 14. This age had stabilized since the mid-20th century as a result of improved living conditions and nutritional habits in the popula-tion. However, since the 1990s to date, age at me-narche has steadily fallen to 12 years, with signs of early breast development in 5-to-6-year-old girls.

Precocious puberty is associated with prenatal exposure to estrogenic EDCs.

Reduced female fecundity

Fecundity refers to the female ability to conceive, whereas fertility implies the potential to carry a pregnancy to term. Estimates show that at least one in ten European couples has difficulty con-ceiving, a significant cause of personal suffering and economic expense for families that seek as-sisted reproductive treatments.

Reduced fecundity is caused by damage to ova and alterations in the menstrual cycle. It is also associated with the alteration of neuroendocrine, endocrine, and paracrine processes that regulate ovogenesis, follicular development, and ovula-tion. Certain chemicals, such as organochlorine compounds, may alter these processes.

Polycystic ovary syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects several bodily systems and causes menstrual dysfunction, infertility, hir-sutism, acne, obesity, and metabolic syndrome, among other medical conditions, with significant psychological, social, and economic impact. Poly-cystic ovary syndrome is the most common fe-male endocrine disorder during the fertile period, with a prevalence of 18 percent in studied cases.

PCOS is associated with an excess of androgenic hormones. Androgenic EDCs include some flame retardants (hexabromocyclododecane, penta-bromodiphenyl ether, and hexabromodiphenyl ether) and certain antibacterial agents such as triclosan, used in some cleaning products and soaps.

Reduced fertility and congenital damage

Fertility problems continue to grow among the European and Spanish populations, occasionally reaching epidemic levels.

Exposure to EDCs is related a series of disorders and medical conditions such as spontaneous abortion (miscarriage), ectopic pregnancy, fetal death, stillbirth, preterm birth, low birth weight, sex-ratio alterations (numbers of male and fe-male babies), and congenital defects.

Miscarriages, preeclampsia, and intrauterine growth restriction (IUGR) are among the most common pregnancy complications caused by altered embryo implantation. Many researchers believe that these disorders are associated with the process of endocrine regulation (preparation of the uterus for pregnancy during the menstrual cycle).

Other endocrine disorders like diabetes, hypo/hyperthyroidism, oligomenorrhea, PCOS, hyper-androgenemia, and hyperprolactinaemia may be causes of miscarriage. Altered progesterone lev-els have also been associated with ectopic preg-nancy and reduced fetal and placental growth, whereas altered estrogen levels are related to variation in sex ratios and certain kinds of con-genital damage.

Some of the EDCs associated with fertility prob-lems and congenital defects include DES, bis-phenol A (BPA), organophosphorus compounds, organochloride compounds (DDT, pentachloro-phenol, PCBs and PCDF), polybrominated biphe-nyls (PBB), and lead.

Endometriosis

Endometriosis is a common gynecological condi-tion in which cells from the lining of the uterus (endometrium) appear and flourish outside the uterine cavity, most commonly in the abdominal cavity. It can cause chronic pelvic pain and infer-tility.

Endometriosis is believed to be caused by the combined effect of genetic predisposition, al-tered immune and hormonal response, and envi-ronmental factors. The prevalence of endometrio-sis varies between 6 and 15 percent of women of childbearing age, and is present in up to 50 per-


cent of cases of pelvic pain and infertility. Endo-metriosis is associated with chemical exposure, namely to bisphenol A and B, phthalates, organo-chlorine pesticides, polybrominated biphenyls, polychlorinated biphenyls, and dioxins.

Uterine fibroids

Uterine fibroids (myomas) are noncancerous smooth muscle tissue tumors that originate in the smooth muscle layer (myometrium) of the uterus. Due to their location in the uterus and the pelvic cavity, they may cause menorrhagia (unu-sual and abnormally heavy menstrual periods), abdominal pain, pelvic organ prolapse, infertility, and complications during pregnancy. Uterine fi-broids are the main reason for hysterectomy (sur-gical removal of the uterus). They affect 25 to 50 percent of women, and given their hormone-de-pendent nature, the role of EDC exposure in their development is a topic of medical interest. They have been associated with exposure to heavy metals, polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides, polychlorinated biphe-nyls, polybromated flame retardants (polybromi-nated diphenyl ethers or PBDEs), and bisphenol A.

1.3.1.2. Tumors in hormone-dependent organsBreast cancer

The incidence of breast cancer has grown, caus-ing great concern in industrialized countries.

Risk factors include reproductive determinants (age of menarche and menopause, number of children and age of first delivery, duration of the breastfeeding period), genetic predisposition, and exposure to environmental pollutants. The most critical periods are those in which breast tissue is more vulnerable, that is, during puberty and uterine development.

Although its development mechanism has not been accurately described, researchers have ob-served that breast cancer is hormone dependent and is associated with exposure to estrogenic EDCs such as polychlorinated biphenyls, polycy-clic aromatic hydrocarbons (PAHs), dioxins, chlo-rinated furans, and organic solvents. Research conducted on Spanish women showed a relation-

ship between breast cancer and the total load of estrogenic chemicals they are exposed to, prov-ing that the combined effect of various pesticide compounds and chlorinated industrial chemicals affects breast cancer incidence, even though ex-posure to such chemicals separately does not (see the section on combined effects on page 13).

Prostate cancer

Prostate cancer is among the most frequent cancers in European men. There has been a dra-matic increase of prostate cancer incidence in all European countries, reaching 24–114 cases per 100,000 inhabitants. Androgenic hormones play a key role in the etiology of prostate cancer. Re-search has shown that high levels of testosterone and its metabolite DHT increase prostate cancer risk. Prostate cancer incidence is related with ex-posure to EDCs, particularly organochlorine and organophospate pesticides during their manu-facture and application, as well as to PCBs, cad-mium, and arsenic.

Testicular cancer

Testicular cancer has reached epidemic propor-tions during the last three decades and has be-come the most frequent malignant neoplasms in men between ages 15 and 34, with a general incidence of 12 cases per 100,000 inhabitants in Europe. The reduction of androgenic action dur-ing the fetal period is among the risk factors.

Several organochlorine EDCs are associated with testicular cancer, among them p,p’-DDT, PCBs, and other organochlorine pesticides. As with breast cancer, the additive effect of exposure to a combination of estrogenic EDCs is considered a risk factor.

Thyroid cancer

Thyroid cancer is among the most prevalent dis-eases in young women. Its worldwide incidence is 1.18 per 100,000, lower than other tumors. Thy-roid cancer is three times more frequent in wom-en, affecting mostly those between ages 15 and 44. Genetics plays a key role as a risk factor but does not explain the sharp increase of this type of cancer in recent years.


Several EDCs act as thyroid antihormones, alter-ing the availability of thyroid hormones. Exposure to chemicals that may alter the HPT (hypothala-mus-pituitary-thyroid) axis contributes to the progression of the disease. Among the EDCs as-sociated with thyroid cancer are several organo-chlorine compounds as dioxins, PCBs, pesticides, and solvents.

1.3.1.3. Alterations in the devel-opment of the neurological system

Disorders in the development of the neurological system include the following conditions:

• Cognitive, learning, and memory disabilities• Autism, attention deficit-hyperactivity disor-

der (ADHD), mental retardation, and cerebral palsy

• Neurophysiological deficits: development milestones, cognitive functions, and behavio-ral problems

• Motor deterioration, memory loss, and subtle behavior changes

• Movement disorders (hypotonia, hyporeflexia, affected motor development), generalized slowing, and significant IQ deficit

• Sensory deficits including ototoxicity and vi-sion defects

• Aggressive behavior• Altered behavior during play• Birth defects such as neural tube defects

U.S. data show an increase of neurological dis-orders during embryogenesis in recent years, of which some 25 percent are considered to be the result of a combination of genetic and environ-mental factors. Hundreds of thousands of children suffer from mental disabilities such as mental re-tardation, learning problems, autism, and ADHD.

Over 10 percent of children suffer from learning disabilities and 17 percent are affected by deaf-ness (hearing impairment), blindness and vision problems, epilepsy, speech problems, and emo-tional disorders.

Endocrine mechanisms involved in neurotoxicity during embryogenesis include interference with

neuroendocrine function (hypothalamus-pitu-itary), a key element in sexual and reproductive behavior, as well as interference with circulation hormones (thyroid hormones and the andro-gens/estrogens that regulate them).

The endocrine mechanism most commonly relat-ed with developmental neurotoxicity is thyroid disorder. A bibliographic search on 48 EDCs in 2004 showed that 50 percent of these chemicals had neurotoxic potential. Among them are or-ganochlorine compounds (PCBs, dioxins, furans), brominated flame retardants (BFR), perchlorate, pesticides, bisphenol A, perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), phtha-lates, ultraviolet filters (4MBC, OMC, BP2 BP3), and heavy metals such as lead, mercury, and ar-senic.

1.3.1.4. Metabolic disorders

Metabolic syndrome, diabetes, and obesity are three metabolic conditions associated with en-docrine disruption whose global incidence has grown significantly. Obesity affects 150 million adults and 15 million children in Europe (20 per-cent of adults and 10 percent of infant popula-tion). Twenty-three percent of Spaniards over 18 are obese, a condition that affects 35 percent of the population over 65. In addition, 6 percent of Spanish adults suffer from diabetes, a disease whose treatment costs 6 percent of the Spanish healthcare budget.

Scientists have suggested several mechanisms by which chemical exposure contributes to obesity, such as the alteration of metabolic set-points, disorders of appetite control, and the alteration of lipid homeostasis during development. Although fetal development is a critical period (since the reprogramming of gene expression through epi-genetic changes may favor future obesity prob-lems), adult exposure to certain chemicals can also cause obesity.

The alteration mechanism associated with type 2 diabetes is the stimulation of estrogenic recep-tors ER-alpha from pancreatic ßeta cells, leading to excess insulin signaling. This can cause insulin resistance in the liver and muscles, as well as beta cell exhaustion.26

26 Angel Nadal, Paloma Alonso-Magdalenab, Sergi Sorianoa, Ivan Quesadaa, Ana B. Roperoa The pancreatic _-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes. Molecular and Cellular Endo-crinology 304 (2009) 63–68 doi:10.1016/j.mce.2009.02.016.


EDCs that may influence the development of such conditions include pesticides and biocides (chlorpyrifos, diazinon, dichlorvos, and carba-mates), phthalates, bisphenol A, polyphenols, metals and organometallic compounds (lead, ar-senic, tributyltin), and other environmental and occupational pollutants such as diesel exhaust.

1.3.1.5. Neuro-immuno-endo-crine disorders

A number of disabling disorders (myalgic enceph-alopathy, otherwise known as chronic fatigue syndrome or post-viral fatigue syndrome; fibro-myalgia; and multiple sclerosis) have increased dramatically over the last few years, causing sig-nificant illness and suffering to the affected indi-viduals and their families.

The global prevalence of myalgic encephalopa-thy (aka chronic fatigue syndrome and post-viral fatigue syndrome) is estimated at 0.004 per-cent—2.54 percent among the general popula-tion and 0.11–2.6 percent in primary care patients. Fibromyalgia, which predominantly affects wom-en, has an incidence in the U.S. of 6.88 cases per 1,000 persons/year in men, and 11.28 cases per 1,000 persons/year in women. Multiple sclerosis mostly affects populations of European descent, its incidence increasing by 3.97 cases per 100,000 population as geographic latitude decreases.

The nervous, immune, and endocrine systems are closely related and regulate each other. Neuro-immuno-endocrine disorders can be attributed to adverse interactions between these systems, and associated with exposure to environmental pollutants, although they have not received the same level of attention as other medical condi-tions to date.

EDCs associated with neuro-immuno-endocrine disorders include polycyclic aromatic hydrocar-bons (PAHs), organochlorine compounds (PCBs, dioxins, pesticides), metals, and organometallic compounds.


1.3.2. Effects on wildlife

Since the mid-twentieth century, scientists and naturalists have documented how different spe-cies (flora and fauna) in different regions of the planet suffer serious effects caused by endocrine disorders associated with exposure to EDCs.27

27 Colborn, Dianne Dumanoski, y John Peterson Myers. “Our Stolen Future” (New York: Penguin Books, 1996). Edición en castellano: Nuestro futuro robado, de Theo Colborn, Dianne Dumanoski y Pete Myers (1997); Ecoespaña y Gaia-Proyecto 2050, Madrid.

In 1952, American scientists observed a significant decline in the Florida bald eagle popula-tion, eventually concluding that 80 percent of bald eagles were sterile.

Otter populations in English rivers began to drop in the 1950s, with this decline continuing at least until the 1970s.

In the mid-1960s, female minks from mink farms on Lake Michigan suffered high mortality rates and reproductive failure as a result of being fed with fish from Lake Michigan tributar-ies contaminated with PCBs.

In 1970, scientists detected high pre-hatching mortality rates and deformities in 80 percent of herring gull chicks of Lake Ontario. Similar conditions were observed in lab chickens treated with dioxins.

In the early 1970s, female-female pairing was detected in western gulls of Southern Califor-nia. This abnormal behavior was later observed in other species of birds in the Great Lakes, Massachusetts, and the Puget Sound.

In the late 1980s, researchers observed that only 18 percent of caiman eggs in Lake Apopka (Florida) were viable and that half of baby caimans died within ten days of birth. Sixty per-cent of males exhibited significantly reduced penis size, i.e., feminized features. Young females exhibited ovarian abnormalities and blood estrogen levels twice the normal for the species. An industrial accident at a Tower Chemical plant had caused a pesticide spill of dicofol and DDT into the lake in 1980.

In spring 1988, a sudden increase in seal mortality was noted in the North Sea region. The sudden death of thousands of seals was caused by a viral infection in 40 percent of the popu-lation. The epidemic was not as devastating in less polluted waters off the coast of Scotland.

Mediterranean striped dolphins were affected by a deadly viral epidemic in the early 1990s. Researchers observed elevated levels of PCBs in the dolphins’ blood—two to three times high-er than in healthy dolphins.

In the 1990s, British scientists observed widespread sexual disruption (feminization) of fish living near sewage treatment plants. The fish also exhibited abnormalities that were not observed in downstream fish. Scientists suspect that degraded detergents, plastics, alkylphe-nols, and other compounds routinely released into rivers are the cause of such abnormalities.


Effects on wildlife due to EDC exposure include:

Invertebrates

The most studied species regarding EDC expo-sure are arthropods and mollusks. Endocrine disorders observed in these species include impo-sex (development of male sex organs by female individuals eventually leading to sterility) and intersex (individuals with both male and female organs), larval mortality, inhibition of metamor-phosis, and reduction of reproductive capability.

EDCs that cause endocrine disorders in arthro-pods include estrogenic EDCs such as BPA. EDCs with endocrine effects on mollusks include tribu-tyltin and xenoestrogens (e.g., nonylphenol and octylphenol).

fish

Induced intersex has been observed in fish ex-posed to effluents of wastewater discharges or sewage treatment plants. These fish also exhibit abnormally high concentrations of vitellogenin (VTG), a provider of egg yolk protein essential for their reproduction. Other effects of exposure to EDCs include altered sex ratios, thyroid disorders, and changes in sexual behavior in affected popu-lations.

EDCs that may affect reproductive capability in fish include:

• Xenoestrogens (phenol derivatives with sur-factant capacity such as nonyphenol, octyl-phenol, and propylphenol)

• Plastifying compounds (bisphenol A and phthalates)

• Mixed chemicals (natural and synthetic estro-gens/alkynols/bisphenol A)

• Aromatase inhibitors such as TBT • Anti-androgenic pesticides (vinclozolin,

prochloraz, and fenarimol)

Exposure to UV filters (3-benzylidene camphor and 2-benzophenone) has recently been associ-ated with endocrine disorders in fish.

EDCs that may alter fish growth and develop-ment include growth hormone disruptors such as PCBs and thyroid disruptors (perchlorate, PCBs, pesticides, and PFOS).

amphibious species

Around 32 percent of known amphibious species are endangered. Environmental pollution is con-sidered a major contributing factor.

Researchers have observed that EDC exposure in amphibious species (most commonly frogs, as the most studied species) leads to induced intersex and masculinization, changes in sexual behavior, and altered metamorphosis and devel-opment.

EDCs associated with endocrine disruption in amphibious species include:

• Antracine and organochlorine compounds• The herbicide Roundup (glyphosate)• Industrial pollutants (PCBs, PBDE, bisphenol

A, phthalates, and effluents from waste treat-ment plants)

Reptiles

Endocrine disruption in reptiles due to EDC expo-sure is generally less explored. There exist some 8,225 known species of reptiles, of which 96 per-cent are snakes and lizards, 3.6 percent are tor-toises, and 0.3 percent are alligators and caimans. EDC research on amphibious species focuses mainly on three of them: the American/Missis-sippi alligator (Alligator mississippiensis) and two species of freshwater turtles (the common snap-ping turtle, or Chelydra serpentina, and Reeve’s turtle, or Chinemys reevesii).

EDC effects on alligators include altered sex ratios (feminization), altered steroid levels, and damage


to the reproductive system such as reduced phal-lus size. EDCs like dicofol, DDD, DDE, and DDT are associated with these effects.

Known effects on turtles include altered sexual dimorphism due to exposure to organochlorine compounds.

Birds

The effects of DDT and its metabolites on birds were among the first types of environmental impact observed in wildlife, becoming widely known after the publication of Rachel Carson’s book Silent Spring in 1962.

Exposure to EDCs causes reproductive disorders, altered egg development, and changes in the sexual behavior of birds.

Reproductive disorders caused by exposure to organochlorine-persistent organic pollutants, or POPs (DDT, PCBs, hexachlorobenzene [HCB], diox-ins, and dieldrin) include abnormalities in sexual organs, altered sex ratio, and impaired fertility.

Thyroid disorders (associated with exposure to PCB, DDT, dioxins, and some PBDEs) are the cause of altered egg development.

Changes in sexual behavior of birds are associ-ated with exposure to organochlorine pesticides, PCBs, and POPs.

Mammals

Mammalian exposure to EDCs has been explored mostly in sea mammals, polar bears, deer, and Mustelidae. In areas contaminated with POPs, the population of Cetaceans (whale family) and polar bears has diminished dramatically. These regions show a correlation between the loss of reproduc-tive capability in Cetacea, Pinnipeds (e.g., seals), and Mustelidae, and POP concentrations in blood and tissues.

EDC exposure in mammals is associated with impaired fertility and abnormalities in the repro-ductive tract observed in deer and panthers in Florida. Thyroid disorders and lesions on the su-prarenal glands have also been detected in these species.


*Polyclorinated biphenyls (PCBs), dioxins (PCDDs), furans (PCDFs)

Source: Andreas Kortenkamp A et al. STATE OF THE ART ASSESSMENT OF ENDOCRINE DISRUPTERSFinal Report. Project Contract Number 070307/2009/550687/SER/D3. Annex 1. SUMMARY OF THE STATE OF THE SCIENCE. Revised ver-sion. Brussels: European Commission, DG Environment, 29 January 2012.

Chemicals of concern

Investigated in connection with…

Human Health Endpoints Wildlife EndpointsM

ale

repr

oduc

t liv

e he

alth

Fem

ale

prec

ocio

us p

uber

ty

Fem

ale

fecu

ndity

Poly

cyst

ic o

vary

synd

rom

e

Fem

ale

fert

ility

Endo

met

riosi

s

Ute

rine

fibro

ids

Brea

st ca

ncer

Pros

tate

canc

er

Test

is ca

ncer

Thyr

oid

canc

er

Dev

elop

men

tal N

euro

toxi

city

Met

abol

ic sy

ndro

me

Inve

rteb

rate

s

Fish

Amph

ibia

ns

Rept

iles

Bird

s

Mam

mal

s

PCBs, PCDDs, PCDFs*

Polybrominated biphe-nylethers (PBDEs)

Perfluorinated com-puonds (PFCs)

DDT/DDE

Other organochlorine pesticides

Organo-phosphate pesticides

Carbamate pesticides

Azole pesticides

Phyrethroid pesticides

Triazine herbicides

Other pesticides

Heavy metals

Alkylphenols, bisphe-nol A, parabens

Phthalates

Pharmaceuticalestrogens

Phytoestrogens

Organotins

Table 5. Relationship of chemicals of concern to human health/wildlife endpoints


1.4. Hazardouschemicals and activitiesOver 1,500 endocrine disrupting chemicals have been identified so far. These substances are found in common consumer products as well as in pes-ticides, biocides, industrial products, and environ-mental pollutants. EDCs include:

• Traditional pollutants such as POPs (PCBs, di-oxins, HCB, organochlorine pesticides, PFOS, PBDE)

• Solvents (styrene, perchloroethylene, trichlo-robenzene)

• Metals (lead, cadmium, nickel, mercury, arse-nic)

• Pesticides (organochlorine and organophos-fate compounds, pyrethrins, pyrethroid)

• Plastics and their components (phthalates, bi-sphenol A)

• Ingredients in cosmetic and cleaning products (parabenes, triclosan)

• UV filters• Components of detergents (alkylphenols)• Environmental pollutants

Within the framework of the European Strategy on EDCs,28 the European Commission ordered in 1999 the first scientific review of endocrine dis-rupting chemicals. The resulting list included 320 chemicals and groups identified as EDCs. The list can be consulted on the European Commission’s website (http://ec.europa.eu/environment/en-docrine/strategy/substances_en.htm#priority_list).29 An update was published in April 2012.

The OECD adopted a work program to develop methods for the identification of EDCs and cre-ated a conceptual framework as well as several guidebooks.30 The guidebooks do not include all of the health effects associated with EDCs (e.g., hormone-dependent cancers, diabetes) nor all fe-tal development effects.

28 Community Strategy for Endocrine Disrupters. A range of substances suspected of interfering with the hormone sys-tems of humans and wildlife COM (1999)706 final. COMMISSION OF THE EUROPEAN COMMUNITIES. Brussels. 17.12.1999

29 http://ec.europa.eu/environment/endocrine/strategy/short_en.htm30 OECD. Conceptual Framework for Testing and Assessment of Endocrine Disrupters. http://www.oecd.org/env/chemicalsafetyandbiosafety/testingofchemicals/50067203.pdf31 http://www.endocrinedisruption.com/endocrine.TEDXList.overview.php.

Several NGOs and trade unions have published EDC lists based on reviews of scientific literature:

TEDX is an organization founded by Theo Col-born, a zoologist and co-author of Our Stolen Future (1997), that disseminates information about the grave effects of EDCs on human health and wildlife. TEDX’s website includes a list of 1,517 endocrine disrupting substanc-es supported by scientific evidence31 (http://www.endocrinedisruption.com/endocrine.TEDXList. overview.php).

RISCTOX is a database developed by ISTAS that includes EDC lists published by the EU and various organizations, including Scorecard and Our Stolen Future. It is available in Spanish at http://www.istas.net/risctox/index.asp

Table 6 shows some of the most common EDC groups.


faMILY CHEMICaL USE CONSUMER PRODUCTS OCCUPaTIONaL aCTIVITIES

PERSISTENTORGaNICPOLLUTaNTS (POP)

PCBs Use is prohibited. Still found in some transformers and electric condensers that use dielectric oil, and in elec-tric parts and construction material residues. PCBs are also residual byproducts result-ing from industrial processes. Waste incineration is a significant source of PCBs.

Sealing and insulating com-pounds used in old electric equipment (buildings)Pollutant in fatty food prod-ucts.

Storage, transport and management of equipment and material contaminated with PCBs:Electric maintenanceMetal / machineryWaste management

POLYCHLORIN-ATED DIBENZODI-OXINS(PCDDs)

Residual byproduct from waste and chlorine–based material incineration/ metal recycling and manufacture/ paper and paper pulp manufacture, chlorophenols, chlorinated herbicides/ chlorine production plants with graphite electrode systems.

Food pollutant ChemistryPaper and paper pulp manu-factureWaste managementMetal

PBBsPBDE

Brominated flame retardants used in plastic and textile products:- Electric and electronic circuits- Car wiring and upholstery /Upholstery in train seats- Panels, carpets and aircraft floor panels- Thermal insulators used in roofs, façades, floors and pipelines - Coating materials used in construction

UpholsteryElectric and electronic equip-mentConstruction materials (insula-tion)Car seat foamsPollutant in household dust

Manufacture of electric and electronic equipmentTransport of wires and cablesConstructionManufacture and mainte-nance of transport equip-ment

ORGANOCHLO-RINE PESTICIDES(DDT,Hexachloroben-zene, Chlordane, Chlordecone, Mirex, Toxaphene, Lindane, Linuron, Acetochlor and Alachlor)

Most commercial applications are prohibitedDDT is still used to control malariaHexachlorobenzene is an industrial byproduct of chlorine

Pollutant in food Chemical industryWaste management

PERFLUORINATED COMPOUNDS (PFos, pfoa)

Multiple uses due to its waterproof and non-stick properties:Non-stick kitchen wareFire fighting foamWaterproof and non-stick coatings in textile, paper and leather products; wax-es, varnishes, paints, cleaning products; coating of metal surfaces and carpetsManufacture of semiconductorsPhotolithographyHydraulic fluids

Non-stick kitchen utensilsTextiles, carpets Dental flossCar seatsFood pollutants

Chemical industryManufacture of plastic itemsTextile industryMetal industryPrintingElectric sectorWaste managementFire fightingGalvanization

UBICUOUS (SHORT-CYCLE) POLLUTaNTS

PHTALATES(BBP, DBP, DEHP)

Mainly used in PVC plasticizers, cellulose, polyvinyl acetate and polyurethaneComponent in certain coatings; insec-ticides and insect repellents; perfumes, nail polish, hairspray and other cosmet-icsLubricant agent in textiles

PVC products: toys, textile, carpets, curtains, floors, hoses, pipelines, windows, etc.Paints and cosmeticsSoft plastic toys, puttyFood pollutantsPollutant in household dust

Manufacture of plastic itemsTextile industryMetal industryManufacture of cosmeticsCleaning services

BISPHENOL-A Used as a raw material in the manufac-ture of paints, epoxy resin plastics and polycarbonatesIntermediate product in the manufac-ture of fungicides, anti-oxidants, dyeing compounds, phenoxy resins, polyester, and flame retardants

It may be released from plastic coatings in canned products, food containers and utensils made of polycarbonateThermal paper printing (faxes and credit card machines)Dental sealing compoundsPollutant in foodPollutant in household dust

Chemical industry: manu-facture, use, transport and packaging of Bisphenol A.ConstructionMetal industryPlastic industry

Table 6. Uses of EDCs most commonly found in consumers’ products and workplaces



ALKYLPHENOLS(nonylphenol eth-oxylate, octylphe-nol ethoxylate and their metabolites (nonylphenol and octylphenol)

Raw material in the manufacture of detergents; emulsifiers, moisturizers and dispersing agents in paints and fungicides PVC anti-oxidants and stabilizers Additive in lubricant oils and contracep-tive foams

DetergentsClothesHousehold pollutant

Chemical industryCleaning servicesAgricultureConstructionManufacture and transforma-tion of PVC

COSMETICS aND HYGIENE PRODUCTS

PARABENSethylparaben, butylparaben, methylparaben and propylparaben

Preservatives used in cosmetic, pharma-ceutical and personal hygiene products

Shampoos, hair conditioners, lotions, creams, gels and other beauty products

Chemical IndustryHairdressingBeauty products

TRICLOSAN5-chloro-(2,4-dichlorophenoxy)phenol

Antimicrobial agent Soaps and detergentsDeodorantsToothpasteCosmeticsTextiles and plastics

Chemical IndustryHairdressingBeauty products

MuskMusk xylene (MX) Musk ketone (MK) galaxolide (HHCB) tonalide (AHTN)

Fragances PerfumesColognesCosmetics Hygiene productsAir freshenersFragrances in consumers articles and toys

Chemical industryRetail businessHairdressingBeauty products

UV SCREENSBenzophenone (BP2)Benzophenone -3 (BP·)4 methylben-zyliden camphor (4MBC)octyl methoxicin-namate (OMC)

Sunscreens Sun blocks AgricultureConstructionGardeningMaintenanceFishing

PESTICIDES, BIOCIDES aND HERBICIDES

ORGANOPHOS-PHATE PESTICIDES(parathion, mala-thion, chlorpyrifos, diazinon, Dichlor-vos, etc.)CARBAMATESPYRETHRINES AND PYRETHROIDSHERBICIDESGLYPHOSATE, ATRAZINE, etc.FUNGICIDESVINCLOCIN AND OTHERS

Fungicides, insecticides, molluscicides, herbicides, disinfectants

PesticidesGardens and orchardsPolluted food

Manufacture of agro-chemi-cal productsAgricultureForestryGardeningBuilding fumigationCleaning servicesMaintenance services

Tributyltin Molluscicides used as anti-fouling agent in ships hulls, buoys, docks.Biocide in bricklayingDisinfectantsBiocide in cooling systems, refrigeration towers in power plants, paper and paper pulp plants, breweries, tanning and textile industries

Naval sector (shipyards)FishingConstructionCleaning servicesCleaning and maintenance of refrigeration towers

INDUSTRIaLPRODUCTS

SOLVENTS1,2,4- Trichloroben-zeneperchloroethyleneoctachlorostyrene

Solvents are used in industry as degreas-ing and cleansing agents and as diluting and carrying agentsSolvents are contained in multiple prod-ucts (paints, varnishes, glues, adhesives, paint strippers, lacquers, insecticides, herbicides, cleaning and dry cleaning products

Paints, varnishes, glues, adhe-sives, paint strippers, lacquers, insecticides, herbicides, clean-ing and dry cleaning products

Chemical industryMetal sectorTextile industryLeather industryCleaning servicesManufacture of electric and electronic parts

RESORCINOL Manufacture of special adhesives and adhesion improvers for tires and woodManufacture of dyeing inks, pharmaceu-tical skin products

Adhesives Wood industryAutomobile industryTextilePharmaceutical industry



STYRENE Main use in the manufacture of polysty-rene and styrene copolymersAdditional uses: manufacture of paints, lacquers and varnishes; paper industry; manufacture of birch panels and poly-mer industry

Paints, lacquers and varnishesPolystyrene foams

Production of styrene and polystyreneManufacture, transformation and application of plasticsMaintenance and cleaning of related industries

CHLORINATED PARAFFINS

Cutting fluids in the metal industryFlame retardants and rubber additives, paints, coatings and sealing compoundsDielectric fluids

Construction materials Metal sectorChemical industryManufacture, transformation and application of plasticsConstructionElectric material

METaLS LEAD In metal form is used in sound and radiation barriers, ammunition, wheel and fishing weights, roof coatings and electronic componentsUsed in metal finishing and welding for metal alloysUsed in chemical compounds as com-ponent of batteries and accumulators; PVC’s rubber and resins; paints, varnishes, polishes and glass

BatteriesHard PVC products: blindsPaintsToy paints Costume jewelryFish, seafood and other food products

MetalFoundriesChemical industryWaste managementGlass manufactureConstruction

CADMIUM Manufacture of nickel cadmium batteries Coatings in galvanoplasty Pigments (is used as yellow pigment) Low fusion alloysWeldingPhosphorescent compounds in TV setsSemiconductorsStabilizers in plastics like PVCPigments in paint manufacture (acrylic, oil)

BatteriesPVC productsPaintsToy paintsCostume jewelryFish, seafood and other food products

Metal Industry

NICKEL Stainless steel manufacture AlloysRechargeable batteriesCatalysisCoin mintingMetal coatings and foundry

BatteriesConsumption of fish, seafood and other food products

ChemistryMetal IndustryWaste management

MERCURY Chlorine manufacture (chlorocaustic industry)Manufacture of vinyl chlorideBatteriesDental amalgamsInstruments of measure and control

Dental amalgamConsumption of fish, sea food and other food products

ChemistryMetal IndustryWaste management

ORGANOSTATIC COMPOUNDSTributyltin (TBT)

Molluscicide used anti-fouling agent in ship hulls, buoys, shipyards, etc.Biocide in cooling systems, refrigeration towers in power plants, paper and paper pulp plants, breweries, tanning and textile industries

Consumption of fish, sea food and other food products

Naval sectorFisheriesConstructionCleaningCleaning and maintenance of refrigeration towers

METaLLOIDS ARSENIC Wood preservativeSemiconductor and LEDAdditives in lead and brass alloysInsecticide (arsenite in lead compounds)Herbicides (Sodium arsenite)Pigments and fireworksDe-staining solution in glass manufac-ture

Consumption of fish, sea food and other food products

ChemistryMetalFoundryWaste managementElectric maintenancePyrotechnics


1.5. Exposure toendocrine disruptorsin Spain

Population exposure

Several studies on the exposure of the Spanish population to endocrine disruptors have been published in recent years.32 Two of these stud-ies, conducted in the Canary Islands33 and Cata-lonia,34 determined the level of concentration of some EDCs in a representative population sample, offering a first glimpse of the social and health significance of population exposure.

The study of the Catalonian population, conduct-ed by Dr. Miquel Porta, analyzed 19 organochlo-rine compounds (DDT and similar compounds, some PCBs, pentaCB, HCB derivatives, and certain HCH isomers) with endocrine disrupting capabili-ty in a sample of 919 persons. At least 3 EDCs were detected in all of the analyzed individuals. Eleven of the 19 analyzed compounds were detected in approximately 60 percent of the population, and all 19 compounds were found in 0.05 percent of the sample population. Over 85 percent of the Catalonian population studied exhibited detect-able levels of p,p’-DDT, p,p’-DDE, PCBs 118, 138, 153, 180, HCB, and ß-HCH, whereas two chemicals were detected in the totality of samples. These results matched those found in similar studies, and data suggest overall exposure of the popula-tion to a mix of EDCs.

Detected concentrations vary depending on the chemical, the individual, and factors like sex, age, and educational level (e.g., the average highest concentration of PCBs was of 0.21 ng/g and for p,p’-DDE it was of 399ng/g). Chemicals with the highest concentrations detected were p’-DDE, HCB, and ß-HCH, with individuals ex-hibiting levels that were 7,700/6,000 and 2,000 times higher than the rest of the group. Women showed higher concentrations of these three compounds, whereas men showed the highest levels of PCBs.

Individuals with lower educational levels exhib-ited higher concentrations of these pollutants. Researchers noted a decline in the concentration of the all the eight POPs as the educational level of individuals increased.

The average concentrations detected (between 0.21 ng/g PCBs and 399 ng/g DDE) exceed the 10ng/g 35 level at which these chemicals have es-trogenic effect.

Exposure during the most vul-nerable periodsFetal sensitivity to EDC exposure has been ex-plored in previous sections. The Spanish Child-hood and Environment Project (INMA) includes a significant number of researchers who study the role of environmental pollutants and their effects on children’s growth and development. Some studies explore the presence of EDCs in the placenta and umbilical cord blood, which may provide a perspective on in utero exposure to en-docrine disruptors.

A research team studying environmental pol-lutants and led by Dr. Nicolás Olea analyzed the presence of 16 pesticides with endocrine disrupt-ing potential in 150 placenta samples from Anda-lusian women. At least one pollutant per sample was detected, with an average of eight pesticides per placenta. Concentrations fluctuated between 0.24 and 5.11ng/g (for aldrin and endosulfan diol), with maximum concentrations between 1.39 and 28.29 ng/g (endosulfan ether and p,p’-DDE).36

The same research team analyzed residues of en-dosulfan (a persistent organic pesticide with es-trogenic effects) in umbilical cord blood from 200 women who gave birth in public hospitals of Gra-nada and Almería (southern Spain). The pesticide was found in 81 percent of the samples, with an average concentration of 13.23 ng/ml and maxi-mum concentrations of 83.22 ng /ml.37

Project INMA also analyzed infant exposure to mercury, an endocrine disrupting metal that al-ters thyroid hormone delivery, interferes with

32 M. Porta, E. Puigdomènech and F. Ballester (Eds.) Nuestra contaminación interna. Concentraciones de compuestos persis-tentes en la población española. Madrid: Los libros de la Catarata, 2009.

33 Ibid 32, Pp 71.34 Porta M, Puigdomènech E, Gasull M y Bosch de Basea M. Op. Cit.35 Ana M. Soto and Carlos Sonnenschein. Op. Cit.36 López Espinosa MJ, Granada A, Carreno J, Salvatierra M, Olea-Serrano F, Olea N. Organochlorine pesticidas in placentas

from Southern Spain and some related factors. Placenta. 2007:28:631-8.


sexual hormones, and causes neurodevelopmen-tal disorders. A study led by doctor Ferrán Bal-lester analyzed mercury in hair samples of 218 newborns and pre-school-age children, and de-tected a total average of mercury (THg) in hair of 0.94 µg/g, which varied from 0.19 to 5.63 µg/g in pre-school-age children. The average detected in newborns was of 1.68 µg/g (0.13–8.43 µg/g).38 In 42 percent of infants analyzed, mercury levels ex-ceeded the reference dose (1 µg Hg/g of hair). An-other study in the same project analyzed mercury in the umbilical cord blood of 1,683 newborns and detected an average level of 8.4 µg/L de THg.39 Sixty-four percent of infants had in utero expo-sure to levels that exceeded 5.8 micrograms of methylmercury per liter of blood (the level con-sidered admissible by the U.S. Environmental Pro-tection Agency). The concentration of mercury in the blood of Spanish infants is among the high-est in the world and is associated with increased fish consumption during pregnancy.

INMA’s researchers assessed the effects of pre-natal exposure and observed higher PCB levels in children with psychomotor disorders.40,41

37 Ibid 32, Pp 81.38 Díez S, Delgado S, Aguilera I, Astray J, Pérez-Gómez B, Torrent M, Sunyer J, Bayona JM. Prenatal and early childhood ex-

posure to mercury and methylmercury in Spain, a high-fish-consumer country. Arch Environ Contam Toxicol. 2009 Apr; 56(3):615-22. Epub 2008 Oct 4.

39 Llop S, Guxens M, Murcia M, Lertxundi A, Ramon R, Riaño I, Rebagliato M, Ibarluzea J, Tardon A, Sunyer J, Ballester F; INMA Project. Prenatal exposure to mercury and infant neurodevelopment in a multicenter cohort in Spain: study of potential modifiers. Am J Epidemiol. 2012 Mar 1;175(5):451-65. Epub 2012 Jan 27.

40 Llop S, Guxens M, Murcia M, Lertxundi A, Ramon R, Riaño I, Rebagliato M, Ibarluzea J, Tardon A, Sunyer J, Ballester F; INMA Project.Prenatal exposure to mercury and infant neurodevelopment in a multicenter cohort in Spain: study of potential modifiers. Am J Epidemiol. 2012 Mar 1;175(5):451-65. Epub 2012 Jan 27.

41 Forns J, Lertxundi N, Aranbarri A, Murcia M, Gascon M, Martinez D, Grellier J, Lertxundi A, Julvez J, Fano E, Goñi F, Grimalt JO, Ballester F, Sunyer J, Ibarluzea J. Prenatal exposure to organochlorine compounds and neuropsychological development up to two years of life. Environ Int. 2012 Sep 15;45:72-7. Epub 2012 May 9.

SUMMaRY

• The results of published studies on EDC exposure show that the general population is in fact exposed to a mixture of EDCs. EDCs are found at different levels in individuals, de-pending on factors like sex, age, educational level, and social status, but they exceed, both on an individual and collective scale, the concentration levels known to cause endocrine disruption. Pregnant women and infants are the most vulnerable population groups due to the high EDC concentrations they are exposed to. If the additive or combined effect is considered, the levels of EDCs in the Spanish population are of great concern.

• Differences in EDC concentration by sex, social status, and educational level show the potential of social and public health intervention to reduce exposure. The results of stud-ies on exposure to EDCs should lead to public health measures to reduce the level of population exposure.


Environmental exposure

There are no specific databases documenting en-vironmental exposure to chemical pollutants in Spain. A comparative description of the current state of affairs in this field can be obtained from dif-ferent emissions/waste registers and from research on pollutants conducted by various scientific teams.

Source: Own research based on data from the Spanish PRTR register.

Table 7. Emissions of selected EDCs in the Span-ish Register of Emissions and Pollutant Sources (PRTR-España), 2010 (tonnes/year)

Pollutant air emissions Water emissionsPOP 33,75 0,53NPE and NP 0,99OPE and OP 0,2Arsenic 4,77 3,23Cadmium 1,5 0,6Mercury 2,1 0,5Lead 40,94 8,4

The Spanish Register of Emissions and Pollutant Sources (PRTR-España)42 provides information on air, water, and soil emissions for 90 polluting sub-stances and groups from a limited number of ac-tivities and industrial facilities that are compelled by law to notify and publish such information (Law 16/2002 on Integrated Pollution Prevention and Control). Table 7 shows data on total emissions of some EDCs included in the register in 2010.

The PRTR register does not include information on the use of pesticides. Estimates compiled by the AQUATERRA Project indicate that only atrazine and simazine (EDC pesticides commonly used in corn and vine crops) represent respective annual loads in the Ebro River of 800 and 500 kg.43

The Environment and Sustainability Institute of the European Commission’s Joint Research Center controls the presence of water-borne pol-lutants to assess the impact of the EU environ-mental policies.44 Table 8 shows data on EDC con-centrations in Spanish surface waters.

Other EDC compounds detected in Spanish riv-ers by university and research center studies in-clude:45

• Pesticides (atrazine, simazine, 2,4-D, MCPA, mecoprop and propanyl)

• Detergents (alkylphenols)• Cleaning products (triclosan)• Industrial pollutants (PDBE, short-chain chlo-

roparaffins)

Researchers have linked the presence of EDCs (alkylphenol) in wastewater to the feminization of several fish species in Spanish rivers. Similarly, alkylphenols and TBT are associated with femini-zation observed in mollusks.46

Household exposureResearch published by Greenpeace on dust sam-ples collected in 22 Spanish households detected phthalates, alkylphenols, organostatic com-pounds, brominated flame retardants, chloropar-affins, and other organic compounds in all sam-ples. Samples were collected in Madrid, Granada, Valencia, Asturias, and León (see Table 9).47

Source: http://fate.jrc.ec.europa.eu/monitoring/monitoring- overview

BarcelonaMorala Nova(Tarragona)

Ber-tamirans(La Coruña)

2,4-D 44,21 27,39 27,17PFOA 42,7 1,65 5,81PFOS 253,97 3,84 6,17

Atrazine Non-detect-able (nd) 79,63 nd

Carbamate 127,84 9,66 157,49Sulfamethoxazole 218,5 11,29 415,89Simazine 54,56 34,58 ndDiuron 278.43 14.32 166.65NPE1C 654.18 864.28 988.47Nonylphenol (NP) 305.29 nd 157.75Bisphenol A 81.75 nd ndtert-OP 191.29 nd nd

Table 8. EDC concentrations (ng/l) in surface wa-ters (Spain, 2011)

42 Registro PRTR España http://www.prtr-es.es. 43 L Damià Barceló y María José López de Alda. Contaminación y calidad química del agua: el problema de los contaminantes emer-

gentes. PANEL CIENTÍFICO-TÉCNICO DE SEGUIMIENTO DE LA POLÍTICA DE AGUAS. Universidad de Sevilla, 24 de enero de 2008.44 http://fate.jrc.ec.europa.eu/monitoring/monitoring-overview45 Laura Vandenberg. Op. Cit.46 Marieta Fernández. Detergentes. Ponencia en el curso Plásticos, detergentes, cosméticos y otras hormonas. UNIVERSIDAD

INTERNACIONAL DE ANDALUCÍA - CURSOS DE VERANO. Universidad de Granada-Hospital Universitario S. Cecilio. Sevilla, 14 a 18 Septiembre 2009.

47 Santillo D, Labunska I, Fairley M y Johnston P. Consumiendo química. Las sustancias peligrosas en el polvo doméstico como indicador de la exposición química en el hogar. Madrid: Greenpeace España. 2003.


Each granule of dust contained an average of 1 milligram of these pollutants, although concen-tration rates of individual chemicals varied de-pending on the sample.

Although comparatively fewer studies have been conducted on exposure through air and house-hold dust than on exposure via food ingestion, results indicate that household concentrations might be primary sources of exposure to some pollutants (organostatic compounds, brominated flame retardants, chloroparaffins).

Results also show extensive EDC contamination of Spanish households. Contact with household dust can be a significant source of exposure, es-pecially for infants, whose metabolism and social behavior imply direct contact, inhalation, and in-gestion of pollutants contained in dust.

48 Contaminants químics, estudi de la dieta total a Catalunya. Generalitata de Catalunya, 2005. http://www.gencat.cat/salut/acsa/html/ca/dir1538/doc10834.html

49 Carmen Cabrera Vique y Miguel Navarro Alarcón. Presencia de metales pesados en la dieta: un control necesario en Ali-mentación, medio ambiente y salud. Observatorio DKV de Salud y Medio Ambiente y ECODES, 2008.

Exposure through foodingestionFood is considered a primary source of exposure of the general population to POPs and certain metals. Research studies on the ingestion of pol-lutants conducted in Catalonia48 and Andalusia49 provide data on exposure to some EDCs through food ingestion in Spain.

The following tables show the results of a study on the population’s diet carried out by the gov-ernment of Catalonia in 2005.

Table 10. Concentration of EDC metals in food, Catalonia (µg/g fresh weight)

food arsenic Cadmium Mercury LeadMeat and meat products 0,0200 0,0063 0,0123 0,0243Fish and seafood 2,2100 0,0362 0,0970 0,0512Vegetables 0,0015 0,0050 0,0005 0,0163Tubers 0,0130 0,0198 0,0030 0,0259Fruit 0,0015 0,0009 0,0005 0,0126Eggs 0,0150 0,0080 0,0080 0,0150Milk 0,0060 0,0015 0,0030 0,0060Dairy products 0,0225 0,0060 0,0115 0,0225Bread and cereals 0,0424 0,0329 0,0300 0,0242Legumes 0,0015 0,0005 0,0005 0,0077Fats 0,0917 0,0080 0, 0300 0, 0300

Source: Contaminants químics, estudi de la dieta total a Cata-lunya. Generalitat de Catalunya, 2005. (Food pollutants in Cata-lonia)

Table 11. Concentrations of organic EDCs in food, Catalonia (µg/g fresh weight)

Source: Contaminants químics, estudi de la dieta total a Catalunya. Generalitat de Catalunya, 2005.

food Dioxins(WHO-TEQ) PaH (µg/kg) HCB (µg/kg) PBDE (µg/kg) Polychlorinated

naphthalenes (µg/kg)Meat and meat products 0,08 13,434 173,2 102,4/116,1 17,59Fish and seafood 0,321 7,894 256,4 325,3/342,5 39,49Vegetables 0,01 0,887 5,8 5,2/10,5 3,38Tubers 0,021 3,606 1,3 0/14,8 2,87Fruit 0,016 0,946 0,7 0/11,5 0,71Eggs 0,071 2,423 182,2 58,3/70,00 23,42Milk 0,014 1,532 12,9 13,2/20,6 0,37Dairy products 0,235 6,636 869,3 34,1/61,8 36Bread and cereals 0,106 14,454 10,6 0/71,4 71,06Legumes 0,023 2,742 0,6 2,0/19,4 3,33Fats 0,303 8,683 136,9 569,3/606,o 447,1

Source: Based on Santillo D, Labunska I, Fairley M y Johnston P. Consumiendo química. Las sustancias peligrosas en el polvo do-méstico como indicador de la exposición química en el hogar. (Hazardous chemicals in household dust) Madrid: Greenpeace. Spain, 2003

Median RankPhthalates (total) 706.2 291-2.644 Alkylphenols (total) <0,1 <0.1-4,5Organostatic compounds (total) 1.495 1.125-1.958Brominated flame retardant (HBCD) 225 190-850Chlorinated paraffins 25 17-41

Table 9. EDC (ng/g) in 22 samples of household dust (Spain)


50 La Vigilància i el control de plaguicides en productes alimentaris i pinsos d’origen vegetal i animal a Catalunya. Periodo 2009-2010. Generalitat de Catalunya. http://www.gencat.cat/salut/acsa/html/ca/dir2911/svc_plaguicides2009-2010.pdf

The results of pollution prevention program stud-ies of Spanish food products show a marked pres-ence of EDCs in all food categories, particularly fish, seafood, and fats. They also show an increase in the number of contaminated samples, as well as the number of pollutants found in different food products.

All of the food analyzed contained EDC residues, but the most contaminated category was by far fish and seafood. Oils, fats, dairy products, and meat showed high EDC concentrations due to the lipophilicity of many organic EDCs, which fa-vors their accumulation in fat.

Studies show that the ingestion of pollutants falls within safe levels established for each chem-ical in adults. However, in the case of children, the levels of ingestion of dioxins and polychlorinated biphenyls exceed those considered safe.

When assessing the ingestion of such pollutants, however, it must be noted that safety levels were established for effects other than endocrine disrup-tion. As described previously, EDCs can have effects at very low doses. Nor does the assessment of in-gestion take into account the combined effects of different EDCs. Table 12 shows different pesticides detected in food in Barcelona (2010) during a re-search program on health and food quality carried out by the Municipal Healthcare Agency (ASPB).50

Source: La Vigilància i el control de plaguicides en productes alimentaris i pinsos d’origen vegetal i animal a Catalunya. Periodo 2009-2010. Generalitat de Catalunya. (Surveillance and control of pesticides in food products, catalonia 2009-2010).

The results of this study show an increase in the number of food samples that failed to comply with acceptable levels of residues and pesti-cides (see Table 13).

Pesticides and metabolites detected in food, Barcelona, 2010

Children’s foods containing vegetables Heptachlor epoxide

Cereales y derivados Ethyl chlorpyrifos, deltamethrin, diphenylamine, pyrimiphos methyl, tebuconazole

Vegetables Azoxistrobín, boscalid, carbendazim (carbendazim + benomil), ciper-metrín, etil-clorpirifòs, clortalonil, dimetomorf, fenhexamida, imida-cloprid, iprodiona, miclobutanil, oxamil, piriproxifèn, tebuconazole, tiabendazole, triadimenol

Fruit Azoxystrobin, boscalid, buprofezin, carbendazim (carbendazim + benomyl), cyporoconazole, difenylamine, dimethoate, fenhexamid, fludioxonil, imazalil, imidacloprid, iprodione, omethoate, procymidone, propargite, tiabendazole, triadimenol

Dried fruit Bifenthrin, carbendazim (carbendazim + benomyl), cyprodinil, fenhexa-mid, fludioxonil, iprodione, myclobutanil, penconazole, pyrimethanil, pyrimiphos methyl, procimidone

Spices Pyrimiphos methyl

Fresh fish DDE p-p’

Table 12. Pesticides and metabolites detected in food, Barcelona, 2010


Source: La Vigilància i el control de plaguicides en productes alimentaris i pinsos d’origen vegetal i animal a Catalunya. Periodo 2009-2010. Generalitat de Catalunya.

Year analyzed samples

No. of analyzed pesticides and

metabolites

No. of different pesticides and

metabolites detected

Samples with-out detectable

residuesSamples with

residues MRLSamples with

residues MRL

2004 285 23-85 6 273 (96%) 8 (3%) 4 (1%)2005 169 40-104 17 135 (80%) 31 (18%) 3 (2%)2006 243 23-106 22 183 (75%) 50 (21%) 10 (4%)2007 178 23-106 25 140 (79%) 31 (17%) 7 (4%)2008 251 24-110 25 208 (83%) 40 (16%) 3 (1 %)2009 335 42-192(1) 32 273 (82%) 48 (14%) 14 (4%)2010 225 42-199(1) 36 161 (72%) 166 (26%) 5 (2%)

Research suggests that food is an important source of EDC exposure in the human popula-tion. This type of exposure affects children in par-ticular, whose ingestion of some pollutants (PCBs and dioxins) might exceed the recommended lev-els of exposure established for other categories.

Occupational exposure

There are few studies on occupational exposure to EDCs in Spain. Epidemiological studies relate some infant health disorders with parental oc-cupation. Additionally, studies on male fertility in industrial sectors (pharmaceutical, plastics, and particularly agriculture) associate reproductive disorders and prostate cancer with pesticide ex-posure.

There are no available data with which to esti-mate occupational exposure to EDCs, however the existing information, although fragmented, could help outline significant traits in this field.

Despite a lack of specific data, it is reasonable to assert that endocrine disruptors affect a vast ar-ray of occupations. A recent job exposure matrix developed by British researchers estimates that exposure to EDCs is possible or probable in 102 different occupations.51 According to such esti-mates, workers in at least 46 occupations would be exposed to EDCs, with exposure to metals in 45, and exposure to PAH, ethylene glycol, and oth-ers in 32 (see Table 14).

51 M. M. Brouwers, M. van Tongeren, A. A. Hirst, et al. Occupational exposure to potential endocrine disruptors: further devel-opment of a job exposure matrix. Occup Environ Med 2009 66: 607-614.

Table 13. Pesticides detected in food, Catalonia 2004–2010


52 García AM, González-Galarzo MC, Benavides FG, Delclòs J, Gadea R, Jiménez R. Proyecto MatEmESp: construccion de una matriz empleo-exposición española. Gac Sanit. 2010; 24 (Especial Congreso 2): 35.

53 Gadea R, Mudemurra L, Jiménez R, Santos T, García AM. Disruptores endocrinos utilizados en la industria textil-confección en España. Med Segur Trab 2009; 55 (214): 111-118.

54 Romano D, Gadea R, Santos T, García AM. Utilización de compuestos orgánicos volátiles (COV) como disolventes en empre-sas españolas. Arch Prev Riesgos Labor. 2011; 14 (1): 28-37.

55 Losilla JM (coord.) Identificación del riesgo químico en el sector de la limpieza en la Comunidad Valenciana. CCOO País Valenciá, 2005.

Table 14. Occupational exposure to EDC groups

Other examples come from a Spanish job expo-sure matrix (MATEMESP) that is currently being developed.52 The matrix estimates that up to 50 percent of employees classified under the cat-egories “painters, varnishers, wallpaper fitters and similar” and “floor layers, welders and simi-lar” might be exposed to aromatic hydrocarbons like toluene and xylene. Furthermore, 30 percent of employees in the category “upholsterers, mat-tress manufacturers and similar” or 43 percent of “machinery operators in shoe manufacture” would be exposed to aliphatic hydrocarbons such as turpentine, naphtha, and hexane.

No exact data on economic activity is available to researchers, but some studies conducted by the Federation of Healthcare and Social Workers (CC.OO.) trade union provide information of interest. A study in the textile sector detected 17 endocrine

Source: M. M. Brouwers, M. van Tongeren, A. A. Hirst, et al. Occupational exposure to potential endocrine disruptors: further develop-ment of a job exposure matrix. Occup Environ Med 2009 66: 607-614.

disrupting chemicals, such as ethyl benzene, di-chloromethane, and vinyl acetate (see Table 15).53 These chemicals were used in a number of activi-ties and workstations, including the manufacture of fibers and tissues, washing stations, textile dyeing, and finishing.

In a project on the prevention of exposure to sol-vents, researchers visited 156 companies in Ma-drid, Valencia, Aragón, and Cantabria, analyzing 656 different products; 22 different EDCs were de-tected.54 Separate research was conducted in the cleaning sector, which employs some 250,000 workers, mostly women. The project allowed re-searchers to identify EDCs contained in cleaning products, such as tetrachloroethynene, dibutyl-phatalate, and styrene, and substances found in detergents, like nonoxynol, polyethylene glycol and octylphenyl.55

EDC group Uses/exposurePAH Produced by incomplete carbon combustion in diesel fuel

Tar industryChlorinated organic compounds By-product in waste incineration, industrial processes (metal, solvent, and

pesticide production)Pesticides Agriculture

Wood treatmentDisinfection

Phthalates Plastic industryProduction and use of solvents, cosmetics, adhesives, and inks

Organic solvents Production and use of paints, adhesives, and lacquersProduction and use of resinsProduction and use of polystyrene plasticsMetal degreasingCleaning products

Bisphenol A Polycarbonate plasticsProduction and use of epoxy resins

Alkylphenols Production and use of pesticides, detergents, and cosmeticsPBDE Production of PCBs, polyester, and rubbersMetals Electric and electronic industry

ConstructionManufacture of batteriesInk production and useDental amalgamPesticides


Table 15. EDCs identified in the textile industry (Spain)

Chemical CaS Industrial processEthylbenzene 100-41-4 Dyeing4,4’ Diisocyanate methylendiphenyl 101-68-8 Pre-treatment

Acrylonitrile 107-13-1 FinishingVynil acetate 108-05-4 FinishingMaleic anhydride 108-31-6 Finishing

2-Butoxyethanol 111-76-2 Maintenance,finishing

Bis (2-ethylhexyl) phthalate 117-81-7 Finishing

Tetrachloroethylene 127-18-4Washing, finishing, quality control, main-tenance, preparation of textiles

Polymer of diglycidyl ether of bisphenol A (epoxy resins)

25068-38-6 Gluing (bonding)

Nonoxynol-9 26027-38-3 FinishingDiisononyl phthalate 28553-12-0 FinishingPoly(oxy-1,2-ethanediyl), alpha-(isononylphenyl)- omega-hydroxy- (non-ylphenol etoxilate)

37205-87-1 Finishing

Permethrin 52645-53-1 FinishingEthanol (anhydrous) 64-17-5 Finishing

Dichloromethane 75-09-2Maintenance,weaving, quality control

Trichloroethylene 79-01-6Washing, finishing, quality control, main-tenance, preparation of textiles, weaving

Nonylphenol etoxy-late 9016-45-9 Finishing

Source: Gadea R, Mudemurra L, Jiménez R, Santos T, García AM. Disruptores endocrinos utilizados en la industria textil-confec-ción en España. Med. Segur. Trab. 2009; 55 (214): 111-118.

The most reliable source for assessing occupa-tional exposure to EDCs is probably the database on exposure to carcinogens (CAREX), which iden-tifies chemicals that are both endocrine disrup-tors and carcinogens.56

CAREX-ESP allows scientists to estimate the number of persons exposed to EDCs. For instance, 138,000 workers were exposed to PAHs, 34,000 to tetrachloroethylene, and 68,000 to lead (see Ta-ble 16).

Table 16. Workers’ exposure to some EDCs (Spain 2004), according to CaREX-ESP

56 IMIM, Midat Mutua, FIOH. Carex-Esp: Sistema de Información sobre Exposición Ocupacional a Cancerígenos en España en el año 2004.

Source: Own research based on data from CAREX-ESP.

These estimates, though partial, show that hun-dreds of thousands of workers are exposed to EDCs in the workplace.

EDC No. of exposed workers

Benzene 128.589

Carbon tetrachloride 6.067

Epichlorohydrin 2.072

PAH 138.181

PCBs 11.302

Tetrachloroethylene 33.911

Styrene 34.919

Trichloroethylene 21.799


2.1. alkylphenols (aPEs)

feminization of fish in Spanish rivers

Feminization of fish due to exposure to estrogenic pollutants was first detected in Spain in 2000 in the Llobregat River basin. The finding took place during the development of a surveillance program on water quality in two of the river’s tributaries, the Anoia and the Cardener. Levels of APEs (detergent components) measured in the water and sediments correlated with estrogenic effects in some fish species, including abnormally high concentrations of plasma vitellogenin in carps (vitellogenin is an egg yolk precur-sor protein used as an indicator of expo-sure to estrogenic compounds), and the existence of intersex fish (fish that devel-oped both male and female reproductive organs).

Fish feminization was observed later in other Spanish rivers, among them the Ebro, Guadarrama, Henares, and Jarama.57

Alkylphenol ethoxylates (APEs) are a group of nonionic surfactants. Commercial formulation usually includes a mixture of several APEs, mostly nonylphenol etoxylate (80 percent of APEs on the world market) and octylphenol etoxylate (20 per-cent).

Nonylphenol etoxylate (9EO); NPE9 (CAS 127087-87-0)

Octylphenol etoxylate (10EO); OPE10 (CAS 9036-19-5)

2. CaSE STUDIES

APEs degrade easily in water and sediments and break down into nonylphenol (NP) and octylphe-nol (OP), chemicals that are far more toxic and persistent, with more estrogenic potential than APEs.

Nonylphenol (CAS 25154-52-3) Octylphenol (CAS 67554-50-1)

Use of APEs Surfactants reduce water’s surface tension, mod-ifying the properties of liquids and facilitating their mixing. APEs are commonly used as:

• Surfactants• Emulsifiers• Wetting compounds• Moisturizers• Inerts (pesticides)• Industrial detergents• Drying agents• Textile and tanning products• Wood distillers• Spermicide, e.g., nonoxynol

The use of APEs in detergents, industrial, and household products is restricted in the EU. How-ever, some imported textiles and leather products contain APEs, which makes washing a primary source of surface water pollution with these chemicals in Europe.

Exposure

Nonylphenol, or NP, has been detected in house-hold air. APEs are common pollutants in waste-water, rivers, and aquifers in relatively high con-centrations. According to the Spanish Register of Emissions and Pollutant Sources (PRTR), 1.19 tonnes of NPEs, NO, OPE, and OP were discharged

57 Marieta Fernández. Detergentes. Ponencia en el curso Plásticos, detergentes, cosméticos y otras hormonas. Universidad Internacional de Andalucía- Cursos de Verano. Universidad de Granada-Hospital Universitario S. Cecilio. Sevilla, 14 a 18 Septiembre 2009.


into Spanish rivers by 12 major water treatment plants in 2010. NPEs have also been detected in fatty foods and consumer products such as food containers, cosmetics, and clothing.

Research conducted by Greenpeace detected NPE residues (in concentrations of 11–1.100 mg/kg) in 52 of 78 textile and footwear products manu-factured by international firms in 18 different countries. After washing, the analyzed clothes contained NPE concentrations of 1.2–350mg/kg.58 NP was also detected in air and dust present in Spanish households (0.1–4.5 APE).59

Effects

Human health

APEs and their metabolites (NP and OP) are toxic chemicals that mimic estrogenic and androgenic hormones and thus affect the reproductive sys-tem.

Wildlife

APEs and their metabolites are very toxic to the aquatic environment. Their EDC effects include:• Feminization of aquatic organisms• Masculinization of aquatic organisms• Reduction of male fertility• Reduction of juvenile survival rates• Altered levels of natural hormones

In male fish, exposure to APEs is associated with the following conditions: • Intersex• Low testosterone levels• Production of vitellogenin• Changes in gonadal tissue • Reduced fertility

In invertebrates (mollusks, insects), OP affects egg production and sexual maturity. It is also as-sociated with imposex/intersex.

Alternatives

Regulatory restrictions promoted the use of sev-eral alternatives to APEs in detergents and clean-ing products (see Table 17).

Table 17. alternatives to the use of alkylphenols as surfactants

58 Greenpeace. Dirty Laundry: Reloaded. How big brands are making consumers unwitting accomplices in the toxic water cycle. Greenpeace International, Amsterdam: March 2012.

http://www.greenpeace.org/eastasia/Global/eastasia/publications/reports/toxics/2012/Dirty%20Laundry%203%20D11.pdf59 Santillo D, Labunska I, Fairley M y Johnston P. Consumiendo Química. Las sustancias peligrosas en el polvo doméstico

como indicador de exposición química en el hogar. Madrid: Greenpeace, 2003.

Chemical CaS Number

C9-11 Alcohol etoxylates (6 EO) 68439-46-3

C12-15 Alcohol etoxylates (9EO) 68131-39-5

Oxirane, methyl-, polymer with ox-irane, mono (2-ethylhexyl) ether

64366-70-7

D-Glucopyranose, oligomeric, decyl octyl glycosides

68515-73-1

Benzenesulfonic acid, C10-13-alkyl derivs., sodium salts

68411-30-3

Sodium dodecyl sulfate 151-21-3

Sodium lauryl ether sulfate 9004-82-4

Sorbitan stearate 1338-41-6

Source: DfE. Alternatives Assessment for Nonylphenol Ethoxy-lates. USEPA May 2012.

Case studies on elimination

CleanGredients®Database: www.cleangredients.org/home

The CleanGredients® database provides informa-tion on alternative chemicals to formulators who seek safer ingredients for cleaning products. The database also showcases surfactants and raw material suppliers that want to promote safer alternatives certified by the Design for the Envi-ronment program of the U.S. Environmental Pro-tection Agency (USEPA). This database includes information and technical specifications on more than 300 surfactants. It also includes information on other chemicals (solvents, chelating agents, fragrances used in cleaning products, etc.).


2.2. Biocides

fumigation of enclosed buildings

Employees and neighbors often suffer adverse health effects caused by toxic chemicals released during the fumigation of enclosed buildings.

The first fumigation accident registered in Spain occurred in Catalonia in August 1994 at the microbiology laboratory of the Vall d’Hebron Hospital. Eight workers were sickened by exposure to biocides (carbamates and pyrethrins) used to fight an ant infestation.

In the period between 1994 and 2001 alone, fumigation caused disabilities in 22 persons and serious conditions in more than 60 female employees in cleaning and management services. The first group was stricken with progressive muscular dystrophy, extreme fatigue, and serious cognitive disorders.

Patients affected by multiple chemical sensitivity syndrome (MCS) cannot toler-ate aerosol sprays or be in contact with synthetic chemical products. They suffer lasting effects such as breathing difficul-ties in crowded spaces and areas of heavy traffic.

Other symptoms found in less-affected patients included headaches, respiratory conditions, diarrhea, smell disorders, and muscle contractions. Some patients also presented with increase of growth hor-mone, which in one case led to the remov-al of the pituitary.

A study conducted by Catalonia’s region-al trade union, CONC, showed that 83.4 percent of the affected individuals were women and only 16.6 percent were men, with an average age of 34. Patients pre-sented with multiple symptoms that es-pecially affected the nervous system.

In 2002, the Supreme Court of Justice of Catalonia ordered the Catalan Institute of Health (ICS, the regional health agency)

to compensate two hospital employees from the Vall d’Hebron Hospital who had sustained irreversible damage (the amount of compensation was of 180,303 euros). The court considered the agency to be responsible for the fumigation acci-dent since the agency managers were re-sponsible for ensuring that the chemicals used “did not constitute any hazard to the employees.”

ABC 28/03/2002, El Mundo 1/02/2001 y PEX 9/06/200

Traces of products used may remain in build-ings and facilities after fumigation, especially when safety requirements are not met, or when the products themselves remain active for long periods of time. These residues might remain on surfaces and in air conditioning and heating pipelines, affecting employees and visitors.

The presence of at least one organophosphate pesticide was detected in most exposure ac-cidents analyzed (and in those that led to per-manent damage). The most frequently detected organophosphate pesticides in these cases were diazinon and chlorpyrifos.

Compounds like pyrethrines and pyrethroids are also frequently detected, with tetramethrine be-ing the most frequently identified product of the latter group. A total of 13 active ingredients have been detected in the pesticides used in different combinations (see Table 18).


Table 18. Chemicals used as biocides involved in building fumigation accidents in Catalonia and their health effects

Exposure

The detected cases in Catalonia are estimated to be 31 percent of real cases with an estimated under-detection rate of 69 percent. Under-detec-tion for the rest of Spain would practically be 100 percent.

According to these data, the estimated preva-lence of exposures per year might affect 4.33 percent of the employed population in Catalonia (124,900). The annual incidence rate would be 19.61 accidents per 10,000 applications and 19.71 affected per 10,000 exposed individuals.60

Chemical Use Health effectsDiazinon1(CAS 333-41-5)

Organophosphate insecticide used in agri-cultural, industrial, and household fumigation

Toxic to the nervous system. Increased risk of brain cancer in infants and non-Hodgkins lymphoma in agricultural workers. Reproductive damage in offspring of lab animals. Endocrine disruptor.

Chlorpyrifos2(CAS 2921-88-2)

Organophosphate insecticide used in agri-cultural and industrial fumigation

Damage to the central nervous system and the immune system. Birth defects. Genetic damage. Development of sensitivity to multiple substances. Possible endocrine disruptor.

Cypermethrin2(CAS 52315-07-8)

Insecticide used in agricultural and indoor fumigation against roaches, mosquitoes, and termites

Damage to the central nervous system. Possible endocrine disruptor. Weakening of the immune system. Birth defects. Chromosome abnormalities. Possible human carcinogen. Persistent in the air and on walls for months after applica-tion. Toxic to bees, caterpillars, fish, and shrimp.

Fenitrothion2(CAS 122-14-5)

Industry Damage to the central nervous system.Possible endocrine disruptor.

Pyrethrins2(CAS 005)

Industry Possible endocrine disruptor.

Alethrin2(CAS 584-79-2)

Industry Contact may cause dermatitis, irritation, allergies. Inhala-tion may cause irritation of respiratory tract, coughing, suffocation, chest pain, runny nose, watery eyes, asthma, and allergic reactions. Probable endocrine disruptor.

Phenothrin2(CAS 26002-80-2)

Household Contact may cause dermatitis, irritation, allergies. Inhala-tion may cause irritation of respiratory tract, coughing, suffocation, chest pain, runny nose, watery eyes, asthma, and allergic reactions. Probable endocrine disruptor.

Nonylphenols and non-ylphenol etoxylates(CAS 9016-45-9) (CAS 9036-19-5) (CAS 26027-38-3)

Inert ingredients in multiple formulations to improve contact with treated surfaces

Persistent in the environment. May damage animal hormone system at very low doses. Estrogenic EDC. Highly toxic to a wide variety of species, causing loss of fertility and motion problems.

Source: Own research based on information from the trade union health and safety quarterly Por Experiencia 9, June 2000.

Effects

Different chemical families are classified accord-ing to their effects on the organism. Generally, all insecticides are considered neurotoxic and af-fect the nervous systems of both insects and hu-mans. The endocrine disrupting effects of a great number of biocides have been observed in recent years. Based on a rough estimate, the most dan-gerous biocides belong to the organochlorine family, followed by organophosphates, carba-mates, pyrethroids, and pyrethrins.61

60 Jordi Obiols y Francisca López. Plaguicidas de uso ambiental: un riesgo poco conocido pero de efectos graves. Por Experi-encia 9, junio 2000.

61 Dossier. Por Experiencia 9, junio 2000.


62 Ibid 7.63 Carme Valls. Riesgo químico: un enfoque de género. Documentos del VI Foro ISTAS de Salud Laboral Retos de la Prevención

del Riesgo Químico. Madrid: ISTAS, 2010.

Organophosphate pesticides block cholinest-erase, a necessary enzyme in brain and nervous system function. The blocking causes excessive and continuous muscle stimulation that leads to abdominal spasms and excessive sweating. Other symptoms of acute exposure include nau-sea, headache, fatigue, vertigo, blurry vision, and pupillary constriction.

Chronic exposure to small doses may affect the nervous system, causing chronic fatigue, head-ache, reduced libido, memory loss, dementia, and muscular dystrophy, symptoms that could persist for up to 10 years after exposure.

Pyrethrins may cause altered skin sensitivity in exposed workers. Symptoms of overexposure in-clude skin numbness, itching, pins-and-needles sensation, and burning. Long-term effects in-clude brain and motion disorders, sensorimotor polyneuropathy, and immunosuppression. Pyre-throids are highly toxic to the aquatic environ-ment, including fish.

Exposure to organochlorine biocides is associ-ated with disabling neuroimmune disorders such as myalgic encephalopathy/chronic fatigue syn-drome/post-viral fatigue syndrome, fibromyalgia, and multiple sclerosis.62

It is hypothesized that repeated exposure to these chemicals causes damage to the hypothalamus-hypophysis axis through physical or chemical microtraumas that eventually cause endocrine disruption and immune disorders.63

Alternatives

The most effective way to eliminate the risks caused by biocide use is the implementation of an integrated pest control program.

These programs aim to achieve long-term pest control results through prevention—by acting on factors that contribute to pest proliferation be-fore outbreaks, and by choosing control strategies that reduce exposure risks. Particularly vulnerable sites and facilities such as schools, health centers, restaurants, and bars may find such alternatives suitable.

An integrated pest control program includes the following activities:

1. Use of control and prevention systems2. Use of chemical treatment only when abso-

lutely necessary3. Choosing less toxic pest control strategies4. Choosing chemical application methods that

carry the lowest possible health risks


Recommendations for pest control by the Catalonian Regional Health agency are found at: http://www.gencat.cat/salut/ctrlplagues/Du13/html/ca/Du13/index.html

The website of the Catalonian Health Agency includes recommendations on implementing in-tegrated pest control programs for both building owners/managers and for agencies and people who request pest control measures. A special section includes tips and recommendations for household pest control.

http://www20.gencat.cat/portal/site/salut/menuitem.f33aa5d2647ce0dbe23ffed3b0c0e1a0/?vgnextoid=aa4ce327b80cf210VgnVCM2000009b0c1e0aRCRD&vgnextchannel=aa4ce327 b80cf210VgnVCM2000009b0c1e0aRCRD&vgn extfmt=default


2.3. EPOXY RESINS –Bisphenol a (BPa)and Epichlorohydrin

Worker exposure to epoxy resins on wind farms

The Spanish company Guascor (contract-ed by Gamesa) set up a temporary facility for the maintenance and repair of wind turbine blades. The activity was organized in tents located within the perimeter of a wind farm. Forty-five employees (mostly women) were involved.

Turbine blade repair tasks included drill-ing, injection of sealing compounds, and painting. Bisphenol A, epichlorohydrin, bisphenol A diglycidyl ether, resin-hard-ening compounds, additives, and solvents were used in the operation.

Sometime after the job began, at least seven female workers experienced men-strual disorders, lactation, headaches, nosebleeds, dizziness, and throat and eye irritation. All of the women experienced these symptoms, and some of the men experienced symptoms as well. Two of the affected workers required permanent portable respirators.

Employees were fully equipped with safety gloves, safety suits, and goggles, however, when the product splashed on protected parts of their bodies, it went through the protective equipment and caused skin burns similar to cigarette burns. When workers complained of diz-ziness, company managers advised them to stay home on sick leave. Some of the women were strongly advised by doctors to avoid pregnancy due to the risk of de-formities.

Physicians from the mutual insurance agency (Spanish benefit society) diag-nosed work-related allergies but the fac-tor that caused the condition was never determined. Given the serious pathology and the number of affected workers, the

Spanish CCOO trade union filed a claim with the Labor Inspector. All affected workers were dismissed.

Berta Chulvi. Trabajadoras desprotegidas ante el ries-go químico. Y por casualidad se descubrió el pastel. Por Experiencia 40, abril de 2008. (Workers unprotected before chemical risk).

Wind turbine blades are manufactured with epoxy resins, which are polymers obtained from a mix of resins and catalyzing (hardening) agents. The most frequently used epoxy resins in this process (95 percent) are based on bisphenol A diglycidyl ether, with epichlorhydrin and BPA as basic ingredients.

The most commonly used hardening compounds include amines, polyamides, phthalic anhydride, and formaldehyde resins. A wide variety of addi-tives are introduced to improve versatility. They include diluents (epichlorhydin), plastifiers, and pigments. Epoxy resins (several CAS numbers) Ingredients:Bisphenol A (CAS 80-05-7) Epichlorhydin (CAS 106-89-8)Bisphenol A diglycidyl ether (CAS 1675-54-3)

Use

Epoxy resins are currently the most widely used polymers in industry, and their use has increased continuously over the past decades. Global de-mand for epoxy resins in 2009 reached 1.8 million tonnes, mainly for industrial applications that in-cluded:

• Electric and electronic equipment (36 percent)• Maritime industries (15 percent)• Powder paint coatings (13 percent)• Civil engineering (10 percent)• Can coatings (9 percent)• Automobile coatings (8 percent)• Composites (5 percent) • Adhesive compounds (4 percent)64

64 http://www.bisphenol-a-europe.org/index.php?page=epoxy-resins


Exposure

The population segments most exposed to epoxy resins include construction workers, electric and electronic manufacturers, composite manufac-turers and painters. A report from the European Agency for Health and Safety at Work (EA OSHA) includes resins as one of the main emerging risks for workers’ health.65

Health Effects

Epoxy resins

The best-known occupational health effects of epoxy resins are skin sensitivity and photosen-sitivity, as well as irritation of the eyes and the airways. Increased use of epoxy resins in the workplace has led to an increase in the number of cases of occupational dermatitis, the most fre-quent cause of allergic contact dermatitis. The incidence of allergic dermatitis in Europe is esti-mated at some 80,000 cases per year (EU-25).66

France included in its national list of occupation-al diseases the “eczema caused by exposure to epoxy resins and their components.”

Epichlorohydrin

Epichlorohydrin is classified as a probable human carcinogen. It is toxic via inhalation, ingestion, or skin contact, and is a neurotoxin that causes re-productive damage and may cause allergic skin reactions. Poisoning symptoms include fatigue, headache, and respiratory symptoms. The sub-stance is included on several lists as a possible endocrine disruptor that may cause reduction of sperm quality, fertility problems, and adverse re-productive effects.

Bisphenol a (BPa)

European regulation classifies BPA as a chemi-cal that may impair fertility, irritate airways, and cause serious ocular damage and allergic skin re-actions.

BPA is also an endocrine disruptor and a known estrogenic chemical since the 1930s. Recent stud-ies have shown that it binds selectively to endo-crine receptors. BPA may stimulate estrogenic receptors in cell membranes at very low concen-trations (parts per billion). It may also alter the ca-pability to synthesize and metabolize hormones and modify hormone concentrations in blood. BPA modifies tissue enzymes and interacts with several hormone response systems.67

The effects of exposure to BPA include changes in gene expression, hormone functions, hormone receptors, lymphocytes, enzymes, and proteins. These changes are expressed in modifications of organ and system function in humans and ani-mals. Effects may vary depending on the organ and the system, and they occur at environmental exposure levels, leading to the conclusion that there are no safe levels of exposure to BPA.68

65 Brun E et al. Expert forecast on emerging chemical risks related to occupational safety and health. European Agency for Safety and Health at Work, 2009.

66 Simon Pickvance, Jon Karnon, Jean Peters and Karen El-Arifi. The Impact of REACH on occupational health. School of Health and Related Research, University of Sheffield, 2005.

67 Rye Senjen & David Azoulay. Blissfully unaware of Bisphenol A. Reasons why regulators should live up to their responsi-bilities. A comprehensive review of the scientific knowledge available regarding controversial Bisphenol A., Friends of the Earth Europe, June 2008. http://www.foeeurope.org/safer_chemicals/Blissfully_unaware_of_BPA_report.pdf

68 TEDX The endocrine disruption exchange. SUMMARY AND COMMENTS ON THE LOW DOSE BPA SPREADSHEET. Septem-ber, 2009 http://www.endocrinedisruption.com/endocrine.bisphenol.summary.php


Pathologies and health conditions associated with BPA exposure include damage to the repro-ductive system, certain types of cancer (breast, prostate), brain and behavior disorders, diabetes, and obesity.

Alternatives

Other materials used in the manufacture of tur-bine blades include:69

• Glass-fiber reinforced plastic (GFRP)• Polyester resins and fiberglass• Polyurethane resins

Case studieson elimination70

LM Wind Power http://www.lmwindpower.com/

The Danish company LM Wind Power, with 12 manufacturing plants across three continents, is the world’s largest manufacturer of wind turbine blades. The company holds a record for the larg-est turbine blades ever made: 73.5 meters for an offshore wind farm belonging to the French com-pany Alstom.

LM Wind Power has used glass fiber and polyester instead of epoxy resins in the manufacture of tur-bine blades since 1978. The company maintains close collaboration with suppliers during the production process to ensure the highest quality. Resins and reinforcing materials have been opti-mized to achieve stronger, uniform, and bubble-free layers.

According to the company, both the raw materi-als and the manufacturing process are consider-ably more expensive when epoxy resins are used rather than polyester and fiberglass.

2.4. Mercury

Spanish newborns contaminated with mercury

In early 2011, Spanish authorities were alerted about alarming levels of mercury in newborn babies. The information was based on data from scientific research con-ducted within the scope of the Childhood and Environment Project (INMA).71 Accord-ing to studies, 64 percent of newborn ba-bies in Spain were exposed to more than 5.8 micrograms of methylmercury per liter of blood (the limit established by the USEPA). Seventy-five percent of babies in the region of Asturias, 68.4 percent in Va-lencia, 64.7 percent in Guipuzkoa, and 49 percent in the municipality of Sabadell ex-ceeded the limit. Furthermore, 10 percent of babies were exposed to 22 micrograms per liter, that is, their exposure exceeded the limit by four times.

Children are particularly sensitive to neurotoxic chemicals such as mercury, and exposure is associated with serious neurological damage. Mercury levels in babies’ blood is linked to their mothers’ ingestion of fish (especially tuna and swordfish) during pregnancy.

El 64 percent de los bebés nace con más mercurio en sangre del deseable (64 percent of Spanish babies overexposed to mercury), El País, 2 julio de 2011. Car-los de Prada. Niños españoles nacen sobreexpuestos a mercurio del pescado (Envir. International, 2011). Fondo Salud Ambiental 31 de enero de 2011. http:// www.fondosaludambiental.org/?q=node/493

69 Richard Stewart. Wind turbine blade production – new products keep pace as scale increases. Renewable Energy Focus.com: 24 January 2012. http://www.renewableenergyfocus.com

70 Ibid. 6.71 Proyecto Infancia y Medio Ambiente (INMA) http://www.proyectoinma.org/presentacion-inma/resultados/#


Uses

Table 19 summarizes the main uses of mercury.

Table 19. Main uses of mercury

Source Category Estimated Global Mercury Consumption in Metric Tons

Estimated Global Mercury atmospheric Emissions in Metric Tons

ASGM 806 350Vinyl chloride monomer manufacture

770 -

Chlor-alkali plants 492 60Batteries 370 20Dental amalgam 362 26Measuring and control devices

350 33

Lighting 135 13Electrical devices 200 26Other 313 29Total 3.798 557

Source: Weinberg, Jack. An NGO introduction to mercury pollu-tion, IPEN, 2010

Exposure72

The first representative analysis of heavy met-als in the Spanish population, commissioned by the Ministry of the Environment, show levels of mercury that exceed by up to 10 times the lev-els found in the populations of Germany or the United States (6.3 mg/l in blood and 1.75 micro-grams/grams in hair), implying a serious risk to the health of pregnant women and babies. The highest concentrations are found among popula-tions of Spanish coastal areas (Andalusia, Murcia, Valencia, and the Balearic Islands). The study cor-roborates the high levels of mercury detected in the infant population by project INMA.

Mercury accumulates in fish tissues due to pollu-tion from wastewaters, especially in urban areas (mercury is used in consumer products, medical equipment, and dental materials, etc.), and from chlorine manufacturing plants that continue to use obsolete technology based on mercury cells. In addition, a significant portion of air emissions, mostly from carbon combustion, is eventually discharged into the sea.

Polluting activities included in the Spanish Reg-ister of Emissions and Pollutant Sources (PRTR) discharged 2.18 Tm of mercury and mercury com-pounds into the atmosphere and 0.97 Tm into the sea, half of which came from urban waste-waters.

The use of mercury cells for the manufacture of chlorine in Spanish plants should have been replaced with diaphragm or membrane cells during the Integrated Environmental Authori-zations grant process. However, the Ministry of the Environment signed a voluntary agreement with the sector that allowed companies to con-tinue using dated technology and therefore con-tinue discharging mercury until the year 2020, provided that discharges did not exceed 0.9 grams of mercury per tonne of chlorine. Even if the industry complies with the agreement, 681 kg of mercury will be discharged into the sea every year.

Carbon is estimated to contain traces of mer-cury (between 0.01 and 1.5 mg of mercury per kg of carbon).73 Considering that 14,709 tonnes of carbon were consumed in Spain in 2009, carbon combustion may have discharged between 0.1 and 22 tonnes of mercury into the atmosphere during that year.

Effects

Mercury is a neurotoxic metal that causes seri-ous intellectual development delays, and dam-ages coordination capability and motor skills in affected individuals. Mercury is also toxic to the reproductive organs; affects the immune system; and causes damage to the kidneys, liver, and cir-culatory system. In addition, mercury is an endo-crine disruptor associated with altered glucose metabolism and diabetes. A persistent and bio-accumulative chemical, it degrades in the envi-ronment into methylmercury, an even more toxic compound.

72 Dolores Romano. Niveles alarmantes de mercurio en la población española. Daphnia 55 (2011).73 Jack Weinberg. Introducción a la contaminación por mercurio para las ONG. IPEN, 2010. http://www.ipen.org/hgfree


Alternatives

Table 20 summarizes the alternatives to the main uses of mercury.

Table 20. alternatives to the use of mercury

Uses alternatives

Mercury cells(chlorocaustics)

Diaphragm cells

Mercury thermometers Aneroid, electronic alter-natives

Mercury sphygmoma-nometer

Aneroides, electrónicos

Gastric tubes Tungsten gastric tubes

Batteries Rechargeable batteries, mercury-free batteries

Fluorescent lamps LED lamps

Dental amalgam Ceramic

Source: Own research based on Weinberg, Jack. An NGO intro-duction to mercury pollution, IPEN, 2010


Elimination of mercury from health centers in aragón74

The Regional Healthcare Department decided to eliminate the use of mercury in all health centers in Aragón (Spain). The decision was made based upon demands for elimination submitted by the Federation of Healthcare and Social Workers (CCOO) of the Sectoral Commission on Workplace Safety, the major representative body for regional healthcare workers.

Trade union representatives prepared the neces-sary documents for the substitution of mercury and asked the department’s main technical ad-viser to develop a substitution program for the total elimination of mercury in all health cent-ers before the date set by law. The trade union (CCOO) sent a copy of the documents to the head of the regional healthcare agency and managed to bring up the topic for discussion before the agency’s Health and Safety Committee.

The technical section of the regional health de-partment drafted a report (For Application to Cer-tain Medical Equipment Containing Mercury) that assessed the situation and became the starting point for the elimination of medical devices that contained mercury in all regional health facilities.

74 Rubén Eito y Luis Clarimón. Un elemento de cuidado. El mercurio se retirará de los centros sanitarios de Aragón. Daphnia 55 (2011).


2.5. Pesticides

Genital deformities in children of field la-borers (almería)

An increase in genital deformities has been observed in newborns over the last few years. These disorders include un-descended testis (chryptorchidism) and abnormal placement of the male urinary meatus (hypospadias).

A study conducted by the University of Granada on a population of 702 mother-and-newborn pairs detected more fre-quent deformities in children of field labor-ers. Placentas were analyzed for exposure to estrogenic pesticides, and it was found that the total xenoestrogenic load in new-born babies with genital deformities ex-ceeded the load of unaffected children.

Parental exposure to xenoestrogens was also related to higher incidence of de-formities.

Use

Over 350 different pesticides are currently used in the European Union, of which at least 43 have po-tential to affect the endocrine system.75 In 2003, with a pesticide consumption rate of 30,000 tonnes, Spain ranked as the second largest pes-ticide consumer in the EU after France. Pesticides are more frequently used on vegetables (some 15 kg of active substance per hectare), vines (12 kg/ha), and citrus fruits (10 kg/ha).76

The most frequently used active substances in 2003 included:

• Fungicides: sulphur, mancozeb, and folpet• Soil fumigants: 1,3-dichloropropene• Insecticides: methomyl, chlorpyrifos, dicofol,

and organosphosphate pesticides• Herbicides: glisophate

Pesticide sales amounted to 680 million euros in 2010.77

Exposure

Data on exposure to endocrine disrupting pesti-cides in section 1 show the ubiquity of exposure to such chemicals. One hundred percent of the Spanish population shows considerably high blood levels of EDC pesticides. Analysis of umbili-cal cord blood and of placentas, indicating the ex-posure of pregnant women and unborn children, raises concern among researchers.

Effects

Both acute and chronic exposure to pesticides cause serious damage to human health. Although research focuses more on acute exposure, multiple studies published over the last two decades reveal the chronic effects of low-dose exposure, such as cancers including leukemia, and endocrine, im-mune, and nervous system disorders.

Earlier, section 1.3 described the main endocrine-disrupting effects of exposure to pesticides (dam-age to the male reproductive system, precocious female puberty, impaired female fecundity and fertility, endometriosis, breast cancer, prostate cancer, thyroid cancer, neurotoxicity during devel-opment, metabolic syndrome, and obesity, among other health conditions).

Other disorders associated with pesticide expo-sure include Parkinson’s disease, Alzheimer’s dis-ease, and attention deficit-hyperactivity disorder (ADHD).78

Alternatives

Organic farming79

Organic farming is an agricultural production system that produces fresh products relying on techniques that respect natural life cycles.

75 PAN Europe. Disrupting food. Endocrine disrupting chemicals in European Union Food. PAN Europe, 2012.76 Eurostat. The use of plant protection products in the European Union. Data 1992-2003. Luxembourg: Office for Official

Publications of the European Communities, 200777 http://servicios2.marm.es/sia/indicadores/ind/ficha.jsp?cod_indicador=23&factor=presion78 PAN Europe. Health effects of pesticides. An impression of recent scientific literature August 2010. http://www.pan-europe.info/Campaigns/pesticides.html79 http://ec.europa.eu/agriculture/organic/organic-farming/what-organic_es


Organic farming includes a series of goals, princi-ples, and common practices aimed at minimizing the environmental impact of human activity and supporting the most natural farming methods possible.

Organic farming techniques include:

• Crop rotation• Strict limitations on the use of pesticides and

synthetic fertilizers• Limited use of genetically modified organisms • Natural fertilization methods such as green

manure• Selection of vegetable species

Case study on elimination

Organic farming cooperative (aGRIECO): http://www.agrieco.es

AGRIECO is an association of organic fruit and vegetable farmers located in the municipality of Pechina, Almería, in southern Spain. The associa-tion consists of 10 founding and 30 collaborating farmers who practice intensive organic farming on 120 hectares. They also own a 4,000-square-meter (43,056-square-feet area for the handling and packaging of products and a 1,100-square-meter (11,840-square-foot) storage facility for the sale and distribution of organic produce.

Farmers use several alternatives to chemical pesticides such as biological pesticides and her-bicides, soil management, increased biodiversity, and the deployment of repellent and reservoir plants (lantana, rosemary, thyme, peppermint).

During the 2005–2006 crop season, AGRIECO’s sales volume reached 3 million kilograms net with a staff of 90 workers.

Eighty-five percent of the farm’s production is exported to foreign supermarket chains in Hol-land, Denmark, Sweden, Austria, Ireland, France, Germany, Eastern Europe, and Canada.


3.1. EU regulationsEU legislation and environmental regulations control the marketing of chemicals and consum-er products containing EDCs.

3.1.1. Community Strategy for Endocrine Disruptors

In 1999, the European Commission published the Community Strategy for Endocrine Disrup-tors—COM (1999) 706—which established the EU guidelines for medium- and long-term action to address the health and environmental risks of EDCs.80 The European Commission published a series of reports in 2001, 2004, and 2007 on the implementation of the strategy.81

The strategy includes the following:

Short-term actions

• Establishment of a priority list of substances to further evaluate their role in endocrine dis-ruption. This list has been published in the EDC section of the Commission’s web page of the Commission and is currently being re-vised.82

• Measurement of EDC levels in food and the environment.

• Identification of vulnerable groups in the pop-ulation, e.g., children, for whom special consid-eration is necessary from a consumer policy point of view.

• Creation of an international network to coor-dinate exchange of information as well as re-search and monitoring.

• Collect, exchange, assess, and provide informa-tion on EDs to the public in consultation with stakeholders.

Medium-term actions

Actions focus on EDC identification, coordination, and funding. They have been funded through EU framework research and development programs and include:

• Identification and assessment of endocrine disruptors

• Research and development• Identification of substitutes and voluntary ini-

tiatives

Long-term actions

These actions address the need to update, amend, or adapt existing regulatory instruments in order to protect human health and the environment. They include:

• Testing and assessment methods• Classification and labeling• Review of existing regulation on pesticides,

biocides, and consumer products• Review of existing environmental regulations

(Framework Water Directive, UNECE protocol on POPs)

The Community Strategy for Endocrine Disrup-tors is currently under review.

3. REGULaTORY fRaMEWORK

80 COMMUNICATION FROM THE COMMISSION TO THE COUNCIL AND THE EUROPEAN PARLIAMENT. Community Strategy for Endocrine Disrupters. A range of substances suspected of interfering with the hormone systems of humans and wildlife COM (1999)706 final. COMMISSION OF THE EUROPEAN COMMUNITIES. Brussels. 17.12.1999

81 COMMISSION STAFF WORKING DOCUMENT on the implementation of the “Community Strategy for Endocrine Disrupt-ers” - a range of substances suspected of interfering with the hormone systems of humans and wildlife

(COM (1999) 706), (COM (2001) 262) (SEC (2004) 1372) and SEC(2007) 1635).82 http://ec.europa.eu/environment/endocrine/strategy/short_en.htm


3.1.2. REaCH RegulationThe use of endocrine disrupting chemicals is subject to authorization under article 57.f of the REACH regulation (1907/2006).83

So far, there are no specific guidelines for the iden-tification and assessment of endocrine activity by EDCs. The deadline for the drafting of guidelines expires on December 9, 2013. However, the Eu-ropean Chemical Agency (ECHA) has already in-cluded one EDC, 4-tert-nonylphenol, in the list of Substances of Very High Concern (SVHC), which are candidates for authorization.

3.1.3. Regulation on the Marketing of Pesticides

The new Regulation on the Marketing of Pesticides (1107/2009)84 prohibits the of use of endocrine dis-ruptors (Annex II 3.6.5). According to this law: “an active substance, safener or synergist shall only be approved if, on the basis of the assessment of Com-munity or internationally agreed test guidelines or other available data and information, including a review of the scientific literature, reviewed by the Authority, it is not considered to have endocrine disrupting properties that may cause adverse ef-fect in humans, unless the exposure of humans to that active substance, safener or synergist in a plant protection product, under realistic proposed conditions of use, is negligible, that is, the product is used in closed systems or in other conditions ex-cluding contact with humans and where residues of the active substance, safener or synergist con-cerned on food and feed do not exceed the default value set in accordance with point (b) of Article 18(1) of Regulation (EC) No 396/2005.”

Such authorizations shall be granted once, for a period not exceeding five years.

The regulation also states that by 14 December 2013, the Commission shall present to the Stand-ing Committee on the Food Chain and Animal

Health a draft of the measures concerning spe-cific scientific criteria for the determination of endocrine disrupting properties to be adopted in accordance with the regulatory procedure with scrutiny referred to in Article 79(4). The European Commission has appointed a group of experts to oversee this task. The same criteria will be applied with regard to REACH regulation, the Regulation on Biocides, and any other European regulation on EDCs (e.g., the Framework Directive on Water).

3.1.4. Regulation onBiocides

The new regulation on biocides (528/2012)85 pro-hibits “active substances which ... are considered as having endocrine-disrupting properties that may cause adverse effects in humans” (Art. 5.1.d). Criteria for EDC identification will be established by the afore-mentioned group of experts.

3.1.5. EU action regarding bisphenol a in baby bottles

Following a citizen-supported European cam-paign to ban BPA and the implementation of measures by several countries, on November 26, 2010, the Directorate General for Health and Consumers announced the total ban in the EU of baby bottles containing BPA. Manufacture was banned beginning in March 2011 and marketing since June 2011.

83 REGULATION (EC) No 1907/2006 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 18 December 2006b concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agen-cy, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC Brussels: Official Journal of the European Union, 30.12.2006.

84 REGULATION (EC) No 1107/2009 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 21 October 2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC. Brus-sels: Official Journal of the European Union, 24.11.2009. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:309:0001:0050:EN:PDF

85 REGULATION (EU) No 528/2012 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 22 May 2012 concerning the making available on the market and use of biocidal products. Brussels: Official Journal of the European Union: 27.6.2012.


3.2. National regulationsSeveral EU countries have banned certain uses of EDCs:86

3.2.1. Regulation on BPaDenmarkIn March 2010, Denmark appealed to the precau-tionary principles to introduce a temporary ban on BPA for products that come in contact with food for children under age three.

franceIn June 2010, the French government temporar-ily suspended the use of BPA in baby bottles. In October 2011, the French National Assembly adopted the ban on BPA for all food containers. This decision must be ratified by the Senate and will take effect in 2013 for any food container for children under 13, and will apply to all food con-tainers in 2014.

SwedenIn July 2010, following the Danish initiative, the Swedish government published a press release on the future ban on BPA in baby bottles.

austriaIn September 2010, the Austrian Ministry of Healthcare announced its intention to ban BPA in children’s products if the EU did not adopt meas-ures to protect infants.

GermanyIn June 2010, the German Ministry of the Envi-ronment published a press release recommend-ing that manufacturers and consumers follow the precautionary principle and use alternative chemicals and products.

BelgiumIn January 2012, the Belgian parliament banned the use of BPA in food containers for children un-der three. The measure takes effect September 2013.

3.2.2. Regulation on para-bens and other EDCs

Denmark Denmark was the first EU country to ban para-bens in lotions and cosmetics for children under three.

franceIn May 2011, the French National Assembly sup-ported a proposal for the ban of parabens, phtha-lates, and alkylphenols. The measure is pending approval by the Senate.

3.2.3. Spanish regulationsThe Spanish government has not introduced any initiatives regarding the ban of EDCs. So far it has only adopted EU directives (such as the ban on the marketing of baby bottles containing BPA).

The only significant improvement in this sense was the introduction of an explanatory note (ti-tled “ED”) on endocrine disruptors in the list of limit values for occupational exposure to chemi-cal agents published every year by National Insti-tute of Occupational Safety and Health87 The ED note specifies that “no limit values have been as-signed to these agents in terms of health effects and endocrine disruption to justify adequate health surveillance.” To date, the Task Force on Limit Values of the National Health and Safety Commission has only considered the first list of endocrine disruptors published in the first report on the implementation of the Community Strat-egy (2001).

86 A CHEM Trust and HEAL briefing: Regulating chemicals with endocrine disrupting properties. May, 2012. http://www.env-health.org/IMG/pdf/36-_heal_ct_edc_criteria_briefing_paper.pdf

87 INSHT. Límites de exposición profesional para agentes químicos en España. Madrid: Instituto Nacional de Seguridad e Higiene en el Trabajo, 2012.


Scientific research shows that endocrine disrup-tors have special characteristics that call for new policies to protect human health and the natural environment (see section 1.2).

The characteristics of endocrine disrupting com-pounds may be summarized as follows:

• May cause harm at very low doses: Exposure levels that may damage human health are ex-tremely low (on the level of parts per trillion). The population is currently exposed to such levels as a result of air pollution in households, food, or pollutants contained in consumer products.

• Timing of exposure may be even more signifi-cant than level: Unborn children and infants are particularly vulnerable to EDCs as these stages of development are especially sensitive to endocrine disruption. The damage caused in these periods can have lifetime health ef-fects.

• There is a nonlinear dose-effect relationship: Damage can occur at very low doses whereas high or intermediate doses might have no ef-fect at all.

• “Cocktail” effect: EDCs can have additive or synergistic effects whereby exposure to low-dose mixtures may imply adverse health ef-fects at exposure levels considered safe for separate components of the mixture. EDCs must therefore be approached as groups of substances rather than as separate substances.

• Effects may pass to future generations as they affect gene expression.

• Latency: Adverse effects may occur many years after exposure. Effects of prenatal ex-posure become evident mostly during adult-hood. Therefore, exposure prevention measures adopted now will improve health indicators in the future.

• Ubiquity of exposure: Studies that monitor the effects of EDC exposure show effects on all age groups in the population. EDCs have been detected in umbilical cord blood, hair, and urine of infants and children, as well as in adult blood and fat tissue. Analysis of food, consumer products, air, water, and household

dust shows the ubiquity of exposure. This cir-cumstance calls for the elimination of sources of exposure to EDCs.

• No safe threshold can be established for EDC exposure.

Such characteristics render inadequate the tra-ditional risk-assessment methods implicit in cur-rent legislation designed to protect the popula-tion and the environment from EDCs. This new health and environmental challenge calls for a new paradigm. It also requires the application of precautionary principle and the adoption of ur-gent measures aimed at:

• Eliminating or reducing exposure to EDCs when possible

• avoiding the exposure of children, pregnant, breastfeeding women, and women of repro-ductive age

• Establishing new identification and testing methods that include chemicals that may in-terfere with the hormone system

4. PROPOSaLS


a series of opportunities will emerge in the up-coming period. They include:

Review of the Community Strategy for EndocrineDisruptorsThe Community Strategy for Endocrine Disrup-tors, initially published in 1999, is currently being reviewed, the main objective being to include in the document the goal of reducing population and environmental exposure to EDCs through the application of the precautionary principle and the setting of specific deadlines for the elimi-nation and restricted use of/exposure to EDCs. The measures reviewed include:

Short-term measures

• Publication of a EU database on EDCs, includ-ing an updated list of chemicals, toxicity in-formation, and references on scientific publi-cations. The list would be a reference for the implementation of EU regulation.

• Development of a specific labeling and classi-fication system for EDCs.

• Development of a more efficient and proactive system for the identification of substances and uses by consumers and workers who wish to take urgent action.

Medium-term measures

The EU must adopt identification and monitoring systems for EDCs that take into account the com-plexity of the endocrine system. Traditional ani-mal testing on mice has proven insufficient; new, improved toxicity tests are required to identify substances associated with increasing disease in the EU such as obesity, diabetes, breast and pros-tate cancer.

Identification and promotion of safer alterna-tives: In 2012, trade unions and NGOs put forth initiatives to disseminate information on safer alternatives, such as the substitution site SUB-SPORT (www.subsport.eu), funded by the LIFE+ program. The EU and Member State authorities must address the limitations of the identifica-tion and promotion of safe alternatives, which include:

• Lack of transparency on substances contained in products

• Lack of information and training of users and consumers on alternatives

• Lack of incentives for the use of alternatives

Long-term measures

A review is necessary of regulations on chemicals, health and environmental protection, and occu-pational health (for instance Directive 92/85/CEE of October 19, 1992, on measures to encourage improvements in workplace safety and health of pregnant, post-partum, and breastfeeding work-ers) to guarantee that regulations include EDC risks.

Reviewing REaCHRegulation

REACH Regulation addresses the registration, evaluation, authorization, and restriction of in-dustrial chemicals. REACH could expedite the elimination of EDCs through restriction and au-thorization processes.

The European Commission is expected to review the conditions for the authorization of EDCs for certain uses before June 2013. In order to elimi-nate exposure to EDCs, the review must include the following:

• Authorization must only be granted if the use of the substance is proven absolutely neces-sary and there are no safer alternatives avail-able. In such cases, authorization must be granted for a limited period only.

• Article 57, on the definition of Substances of Very High Concern, must include specific cri-teria for endocrine disrupting properties, aside from the current criteria for equivalent level of concern (57f).

• CMRs (carcinogens, mutagens, and reprotoxic substances) or PBTs (persistent bio-accumula-tive and toxic substances) must be included in the candidate list for authorization (in order to grant the reviewing of those authorizations when new conditions to authorize EDCs come into force).


Establishing criteriafor EDC identification

Criteria adopted by law must allow identification of the highest possible number of EDCs to which the population is exposed. These criteria must be based on the hazardous characteristics of sub-stances, as in the EU CLP Regulation in the case of CMR substances. In addition, independent sci-entific publications funded by the European R&D Framework Program must be taken into account. This would grant the use of current scientific knowledge on EDCs’ effects and up-to-date iden-tification methods.

National regulationList of occupational limit values for exposure to chemical agents

The list of chemicals under the explanatory note ED (endocrine disruptors) must be extended to include all substances currently included in the European Commission’s list. This will allow com-panies to identify EDCs at workplaces and adopt necessary protections and preventive measures.

Prohibition of EDC exposure for pregnant and breastfeeding workers

Endocrine disruptors must be included in the list of chemical agents to be avoided, according to Royal Decree 298/2009 on the Adoption of Meas-ures to Promote Occupational Health and Safety for Pregnant and Breastfeeding Workers.

RD 298/2009 introduces to Spanish legislation the list of agents that imply health risks for preg-nant and breastfeeding workers and that must be assessed (Annex VII) or avoided (Annex VIII). The list of agents included in this regulation is based on the list published by Directive 92/85/EEC,88 therefore it does not include new scientific knowledge on endocrine disruptors generated in the last two decades.

Banning the production and use of chemicals following the experience of the EU countries with the most advanced healthcare and environmental protection policies

88 Council Directive 92/85/EEC of 19 October 1992 on the introduction of measures to encourage improvements in the safety and health at work of pregnant workers and workers who have recently given birth or are breastfeeding (tenth individual Directive within the meaning of Article 16 (1) of Directive 89/391/EEC).

ENDOCRINE DISRUPTORS

Documents

Transcript of ENDOCRINE DISRUPTORS